A Phase 1 Study of NKX019, a CD19 Chimeric Antigen Receptor Natural Killer (CAR NK) Cell Therapy, in Subjects with B-Cell Malignancies

Abstract Background: B-cell lineage cancers are a worldwide healthcare burden. Over 500,000 new cases of non-Hodgkin lymphoma (NHL) and 50,000 new cases of acute lymphoblastic leukemia (ALL) are diagnosed world-wide each year (seer.cancer.gov, Smith 2015, Solomon 2017). Despite progress in treatment, many patients diagnosed with this heterogeneous group of cancers still succumb to their disease. Recently approved autologous chimeric antigen receptor (CAR) T cells specific for CD19 have altered the treatment landscape for some patients with relapsed or refractory (R/R) B-cell malignancies, though significant toxicities associated with T-cell expansion and the necessity for bespoke manufacturing have limited their use. Natural killer (NK) cells, part of the innate immune system, efficiently recognize transformed cells and are particularly suited to address limitations of the approved CAR T products (Marcus 2014, Morvan 2016). Lacking a T-cell receptor and the consequent clonal expansion, non-engineered NK cells have been safely administered after lymphodepletion without side effects typically associated with T-cell therapies, such as severe cytokine release syndrome or neurotoxicity (Bachier 2020). Allogeneic NK cell-based therapies allow off-the-shelf use, obviating the necessity to wait for manufacture of autologous T-cell therapies. CD19-directed CAR NK cells have been administered safely, with promising preliminary efficacy (Liu 2020). NKX019 is a cryopreserved product, composed of expanded NK cells engineered to express a humanized CAR against CD19, fused to co-stimulatory (OX40) and signaling (CD3ζ) domains to enhance their intrinsic antitumor activity. NKX019 also expresses a membrane-bound interleukin-15 (IL-15) to serve as an autocrine growth factor and thereby increase NKX019 persistence, with an in vivo half-life of over up to 28 days without systemic IL-2 support. Preclinical characterization has shown that NKX019 cells are 10 times more effective at killing CD19+ target cells than non-engineered NK cells, resulting in greater suppression of xenograft tumor models (Morisot 2020). Further, NKX019, unlike CD19 CAR T cells, retained cytotoxicity even when CD19 antigen density was reduced >50x on target cells. Hence, clinical evaluation of NKX019 is being undertaken in this Phase 1 study in subjects with R/R NHL or ALL. Methods: This is a multicenter, open-label, Phase 1 study of NKX019 (Figure). The study will be conducted in 2 parts: Part 1 (dose finding) to determine the recommended Phase 2 dose (RP2D) of NKX019 separately in adult patients with CAR T naïve R/R NHL or B-ALL, utilizing a "3+3" enrollment schema. Part 2 (dose expansion) will further evaluate safety and tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PDn), and antitumor activity of NKX019 using RP2D with separate expansion cohorts for patients with ALL as well as different subtypes of NHL, including a cohort of CAR T pretreated large B-cell lymphoma. NKX019 is being manufactured from NK cells obtained from healthy adult donors. The study evaluates two dose levels of NKX019: 3 × 10 8 and 1 × 10 9 viable CAR+ NK cells. NKX019 will be administered on Days 0, 7, and 14 of a 28-day cycle following standard fludarabine/cyclophosphamide lymphodepletion (Table). Up to 5 total cycles may be administered based on response and tolerability assessed at the end of each cycle. The primary endpoint is incidence of adverse events, dose-limiting toxicities, clinically significant laboratory abnormalities, and determination of the RP2D. Secondary endpoints include evaluation of standard cellular PK parameters, PDn, immunogenicity, and antitumor responses. Subjects will be assessed for efficacy using disease-specific criteria: Lugano classification with LYRIC refinement for pseudo-progression (NHL), 2018 International Workshop (IW) criteria (CLL), 6th IW criteria (Waldenström macroglobulinemia [WM]), and National Comprehensive Cancer Version 1.2020 (B-ALL) (Cheson 2006, Cheson 2014, Hallek 2018, Owen 2013, Brown 2020). Enrollment across multiple sites in the US and Australia is expected to start in the second half of 2021. Figure 1 Figure 1. Disclosures Dickinson: Celgene: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bryant: Jansen, BMS/Celgene, Skyline Diagnostics: Consultancy; Amgen: Honoraria. Borthakur: Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Shook: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rajangam: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: SITC: Honoraria; BMS; Karyopharm; Miltenyi: Research Funding; Agios; NGM Biopharmaceuticals; BeiGene: Consultancy. McSweeney: Kite-Gilead: Consultancy; Kite-Gilead, Autolus, Novartis: Research Funding; Kite-Gilead: Honoraria, Speakers Bureau. Hill: Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AstraZenica: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

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Disease Burden Impacts Outcomes in Pediatric and Young Adult B-Cell Acute Lymphoblastic Leukemia after Commercial Tisagenlecleucel: Results from the Pediatric Real World CAR Consortium (PRWCC)

Blood ◽

10.1182/blood-2020-134472 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Liora M. Schultz ◽

Christina Baggott ◽

Snehit Prabhu ◽

Holly Pacenta ◽

Christine L Phillips ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Disease Burden ◽

Publicly Traded ◽

Advisory Committees ◽

Car T

Introduction: Chimeric Antigen Receptor (CAR) T cell therapy targeting CD19 has shifted our treatment approach for relapsed and refractory (r/r) pediatric B cell acute lymphoblastic leukemia (ALL). The landmark ELIANA pediatric trial studying tisagenlecleucel, CD19-specific CAR T cells, demonstrated a complete response (CR) rate of 81% in 75 infused patients and 12 month overall survival (OS) and event-free survival (EFS) rates of 76% and 50% respectively. Cytokine release syndrome (CRS) and neurotoxicity rates of 77% and 40% were respectively reported. In August 2017, the FDA approved tisagenlecleucel for B-cell ALL that is refractory or in second or greater relapse in patients up to age 25. With CAR commercialization, institutions deliver tisagenlecleucel without the regulation of a clinical study and practices relating to CAR delivery and reporting remain heterogeneous. Here, we report real world clinical outcomes using commercially available tisagenlecleucel for pediatric r/r B-ALL. Methods and Results: Retrospective data were collected from PRWCC member institutions (n=15) and included 200 patients. This includes 15 (7.5%) patients not infused due to manufacturing failure (n=6), death from disease progression and/or toxicity (n=7), or physician discretion following disease remission from prior therapy(n=2). The remaining 185 patients (92.5%) were infused with tisagenlecleucel, including 87% (161) receiving standard-of-care CAR T cell products meeting manufacturing release criteria and 13% (24) receiving CD19-CAR T cells manufactured by Novartis and provided on the managed access program (NCT03601442; n=14) or with single-patient IND approval (n=10). At time of CAR T cell infusion, median age was 12 years (range 0-26) with 40% females and 60% males. Median duration of follow-up at time of analysis was 11.2 months (range 0.2-28.8). The CR rate at 1 month follow up was 79% (156/198) on an intent-to-treat basis and 85% (156/184) among evaluable infused patients. Of infused patients achieving morphologic CR with available testing, 97% (148/153) were negative for MRD by flow cytometry. Duration of remission at 6 and 12 months among patients who achieved CR was 75% and 63% respectively, with 35% (55/156) of responders experiencing relapse. At time of relapse, 41% (21/51) of evaluable patients had relapse with CD19- disease and 59% (30/51) had continued CD19 expression. OS and EFS rates were 85% and 64% at 6 months and 72% and 51% at 12 months, respectively. CRS and neurotoxicity of any grade were seen in 60% (111/184) and 22% (39/181) of evaluable patients with ≥ grade 3 CRS and neurotoxicity rates of 19% (35/184) and 7% (12/181) respectively. One grade 5 CRS and 1 grade 5 neurotoxicity (intracranial hemorrhage) were reported. Post infusion toxicity management included tocilizumab in 26% (47/184) and systemic steroids in 14% (25/184) of patients. Among 181 infused patients with documented disease burden, 51% (95) had high burden (HB) disease , as defined by >5% bone marrow lymphoblasts, peripheral blood lymphoblasts, CNS3 status or non-CNS extramedullary (EM) site of disease; 22% (40) had low burden (LB) disease, defined by detectable disease not meeting the HB criteria; and 25% (46) had no detectable disease (NDD) at time of last evaluation prior to CAR infusion. The morphologic CR rate was lower at day 28 in HB vs. LB and NDD (74% vs. 98% and 96%) and the OS and EFS were lower among patients with HB at 6 mo [OS; 75% (HB), 94%(LB), 98% (NDD), EFS; 50% (HB), 86% (LB), 75%(NDD), p<0.0001] and 12 mo [OS; 58% (HB), 85% (LB), 95% (NDD), EFS; 34% (HB), 69%(LB), 72%(NDD), p<0.0001]. Multivariate analysis will be presented at the meeting. Conclusions: This retrospective, multi-institutional analysis describes real world outcomes using tisagenlecleucel to treat pediatric r/r B-ALL. Early responses at 1 month and OS and EFS at 6 and 12 months are comparable to reported ELIANA trial outcomes. Safety is demonstrated in this cohort with lower rates or CRS and neurotoxicity, likely related to a lower disease burden cohort. Continued relapse and decrease in OS without evident plateau is seen following 6 months post-infusion warranting expanded follow up. Comparative analysis of outcomes in patient cohorts with varying disease burden demonstrate decreased CR, EFS and OS in patients with high disease burden as compared to patients with lower disease burden or no detectable disease at last evaluation prior to CAR infusion. Disclosures Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees. Stefanski:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Margossian:Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Verneris:Fate Therapeutics: Consultancy, Current equity holder in publicly-traded company; Novartis: Membership on an entity's Board of Directors or advisory committees; Bmogen: Consultancy, Current equity holder in publicly-traded company; Uptodate: Consultancy. Myers:Novartis: Consultancy, Honoraria, Other: ELIANA trial Steering Committee, Speakers Bureau. Brown:Jazz: Honoraria; Servier: Honoraria; Janssen: Consultancy; Novartis: Consultancy. Qayed:Novartis: Consultancy; Mesoblast: Consultancy. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Satwani:Takeda: Consultancy; Mesoblast: Consultancy. Curran:Novartis: Consultancy, Research Funding; Mesoblast: Consultancy; Celgene: Research Funding. Mackall:Lyell Immunopharma: Consultancy, Current equity holder in private company; Nektar Therapeutics: Consultancy; NeoImmune Tech: Consultancy; Apricity Health: Consultancy, Current equity holder in private company; BMS: Consultancy; Allogene: Current equity holder in publicly-traded company. Laetsch:Cellectis: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Bayer: Consultancy, Research Funding.

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CD19-Directed CAR T-Cell (CTL019) Product Viability and Clinical Outcomes in Non-Hodgkin Lymphomas and B-Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2018-197 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 197-197 ◽

Cited By ~ 4

Author(s):

Elise A. Chong ◽

Bruce L Levine ◽

Stephan A. Grupp ◽

Megan Davis ◽

Don L. Siegel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Test Results ◽

Advisory Committees ◽

Car T Cell ◽

Release Test ◽

Car T

Abstract Introduction: CTL019 is an anti-CD19 genetically modified autologous T-cell immunotherapy developed at the University of Pennsylvania (Penn) that was recently approved for treatment of relapsed/refractory pediatric and young adult B-cell acute lymphoblastic leukemia (ALL) and adult relapsed/refractory diffuse large B-cell lymphoma (DLBCL) as tisagenlecleucel (Novartis). For ALL, the FDA-approved dose is 0.2 to 5.0 x 106 CAR-positive viable T cells per kg of body weight for patients ≤ 50 kg or 0.1 to 2.5 x 108 CAR-positive viable T cells for pts > 50 kg; for DLBCL, the FDA-approved dose is 0.6 to 6.0 x 108 CAR-positive viable T cells. For CTL019 manufactured at Penn, the dose is determined by flow cytometric staining of CAR-positive T cells, which are cryopreserved in product bags along with replicate aliquots of the final formulation in vials, simultaneously cryopreserved for release testing. The CTL019 product release criteria include a post thaw viability assessment using a vial of replicate aliquot of the final formulation for Trypan blue exclusion or dual fluorescence automated cell counting (Luna-FL, Logos Biosystems). There are no published data examining the relationship between CTL019 viability release testing and clinical outcomes. Methods: We analyzed CTL019 post thaw viability release testing in patients treated on one prospective single institution clinical trial of CD19-expressing non-Hodgkin lymphomas (NHL) (NCT02030834) and two single-institution prospective pediatric ALL clinical trials (NCT01626495 and NCT02906371). Patients were assessed for response to therapy and CAR T-cell expansion. Receiver operating characteristic (ROC) curves were constructed for prediction of complete responses based on sensitivity and specificity of CAR T-cell product post thaw viability release test results. Results: 39 pts with relapsed/refractory NHL (24 diffuse large B-cell lymphoma and 15 follicular lymphoma) were enrolled and received the protocol-specified dose of CTL019. Best response rate was 56% (22/39) complete responses (CR). 123 pts with relapsed/refractory pediatric ALL were enrolled and received the protocol-specified dose of CTL019. Best response rate was 96% (118/123) CR/complete remission with incomplete blood count recovery (CRi). For patients with NHL infused with CTL019, product % viability had a median of 89.8% viability (range: 73.7%-97.7%); product % viability quintiles were as follows: 20%-tile=81.7%, 40%-tile=88.3%, 60%-tile=91.1%, 80%-tile=94.8%). ROC area for NHL patients was 0.47 (95%CI: 0.28-0.65). For patients with ALL infused with CTL019, product % viability had a median of 89.3% viability (range: 56.0%-98.4%); product % viability quintiles were as follows: 20%-tile=82.3%, 40%-tile=87.5%, 60%-tile=90.9%, 80%-tile=94.4%). ROC area for ALL patients was 0.52 (95%CI: 0.32-0.71). For patients with NHL, progression-free survival (PFS) was not significantly influenced by product viability release test results by Cox proportional hazards (HR: 1.0, 95%CI: 0.94-1.09, p=0.7). For patients with NHL, peak CAR T-cell expansion was not significantly correlated with product viability release test results (r2=0.12, p=0.5). Data collection for Cox analysis to investigate the effect of release test viability on PFS and correlation of release test viability with peak CTL019 expansion in ALL is ongoing and will be presented. Conclusions: Our data suggest that, within the ranges obtained in these trials, there is no clear dose-response relationship between CTL019 product viability release test results and clinical response rates in pediatric and young adult ALL or DLBCL. Figure Figure. Disclosures Chong: Novartis: Consultancy. Levine:Cure Genetics: Consultancy; Brammer Bio: Consultancy; CRC Oncology: Consultancy; Incysus: Consultancy; Novartis: Consultancy, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy. Davis:Novartis Institutes for Biomedical Research, Inc.: Patents & Royalties. Siegel:Novartis: Research Funding. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Frey:Novartis: Consultancy; Servier Consultancy: Consultancy. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board. June:Immune Design: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding. Schuster:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.

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Efficacy and Toxicity of JCAR014 in Combination with Durvalumab for the Treatment of Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2018-99-116745 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1680-1680 ◽

Cited By ~ 8

Author(s):

Alexandre V. Hirayama ◽

Jordan Gauthier ◽

Kevin A. Hay ◽

Alyssa Sheih ◽

Sindhu Cherian ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Group 2

Abstract Introduction Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have shown high overall response rates (ORR) in otherwise treatment-refractory CD19+ B-cell non-Hodgkin lymphoma (NHL); however, not all patients (pts) achieve complete remission (CR). PD-L1 expression on tumor cells and/or other tissues could impair the function of PD-1+ CAR-T cells and the efficacy of CD19 CAR-T cell immunotherapy. PD-1 pathway blockade may enhance the function and antitumor activity of CD19 CAR-T cells. Here we report preliminary data from a phase 1 dose-finding study (NCT02706405) of the safety and feasibility of combination therapy with JCAR014 CD19-specific 4-1BB-costimulated CAR-T cells and escalating doses of durvalumab, an anti-PD-L1 monoclonal antibody, in adults with relapsed/refractory aggressive B-cell NHL. Methods Pts are treated in one of two groups. All pts receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine followed by infusion of JCAR014. Pts in group 1 receive the first infusion of durvalumab (225 mg, 750 mg, or 1500 mg) 21-28 days after treatment with JCAR014. Pts in group 2 receive the first dose of durvalumab (7.5 mg, 22.5 mg, 75 mg, 225 mg, 750 mg, or 1500 mg) 1 day prior to JCAR014 infusion. Up to 10 doses of durvalumab are administered after JCAR014 at the highest identified safe dose at 4-week intervals until toxicity or disease progression. We evaluated the safety, tolerability, and efficacy of the combination therapy and the pharmacokinetic profile of JCAR014 after infusion. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, with the exception of cytokine release syndrome (CRS), which was graded according to consensus criteria (Lee, Blood 2014). Positron emission tomography/computed tomography was performed approximately 1, 2, 4, 6, 9, and 12 months after JCAR014 infusion and the best anti-tumor response was reported according to the Lugano criteria (Cheson, JCO 2014). Results Patient characteristics are shown in Table 1. Fifteen pts have been treated, including 6 in group 1 who received post-JCAR014 durvalumab doses of 225 mg (n = 3) and 750 mg (n = 3), and 9 in group 2 who received pre-JCAR014 durvalumab doses of 7.5 mg (n = 1), 22.5 mg (n = 1), 75 mg (n = 3), or 225 mg (n = 4). Durvalumab dose escalation is ongoing. JCAR014 manufacturing was successful for all pts. All pts received 2 x 106 JCAR014 CAR-T cells/kg, except the first 2 pts treated on the study who received 7 x 105 CAR-T cells/kg. Of the 13 pts who received JCAR014 at 2 x 106 CAR-T cells/kg, 5 pts (38%) developed CRS (2 grade 1, 2 grade 2, and 1 grade 4) and one (8%) developed grade 1 neurotoxicity. CRS and/or neurotoxicity occurred within 4 weeks of JCAR014 infusion, and were not observed when durvalumab was administered after JCAR014. With the exception of B cell aplasia, no autoimmune adverse events were observed. Twelve of 13 pts who received 2 x 106 CAR-T cells/kg were evaluable for response. One patient, who had grade 4 CRS and biopsy evidence of extensive CAR-T cell infiltration into persistent sites of disease, elected to receive hospice care and died on day 32 after JCAR014 infusion without full response evaluation. The overall response rate was 50% (5 CR, 42%; 1 PR, 8%). Of the 5 pts who achieved CR, 3 were in CR at the first restaging after JCAR014 and 2 subsequently converted to CR after the first post-JCAR014 durvalumab infusion. Only one patient who achieved CR has relapsed (median follow-up 10.6 months, range 3.7-11.8). Continued stable disease or evidence of regression was seen in 4 of 6 (67%) initially non-responding pts who continued durvalumab therapy (median 5 doses, range 1-6). CAR-T cell counts expanded in the peripheral blood within 14 days of JCAR014 infusion in all pts. Higher peak and day 28 CAR-T cell copy numbers in blood by qPCR were observed in responding pts. CAR-T cells were detected for a median of 5.1 months (range, 1.7 to 9.1 months) in responding pts. In vivo re-accumulation of CAR-T cells after the first post-JCAR014 durvalumab dose was observed in the blood of two patients in group 2. Conclusion The combination of JCAR014 with durvalumab for the treatment of adult pts with aggressive B-cell NHL appears safe; however, dose escalation is ongoing. Complete responses were observed both at initial restaging after JCAR014 infusion, and also subsequently in pts continuing durvalumab therapy after initially failing to achieve CR. Disclosures Hirayama: DAVA Oncology: Honoraria. Hay:DAVA Oncology: Honoraria. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Homology Medicine: Consultancy; Magenta: Consultancy; Rocket Pharmaceuticals: Consultancy. Shadman:Verastem: Consultancy; Beigene: Research Funding; Mustang Biopharma: Research Funding; Gilead Sciences: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Research Funding. Cassaday:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Research Funding; Incyte: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Riddell:Cell Medica: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; NOHLA: Consultancy. Maloney:Roche/Genentech: Honoraria; Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; GlaxoSmithKline: Research Funding; Seattle Genetics: Honoraria. Turtle:Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; Bluebird Bio: Consultancy; Gilead: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Caribou Biosciences: Consultancy; Aptevo: Consultancy.

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Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2019-125995 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1587-1587

Author(s):

Ian W. Flinn ◽

Jason R. Westin ◽

Jonathon B. Cohen ◽

Luke P. Akard ◽

Samantha Jaglowski ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Advisory Board ◽

Phase 1 Study ◽

Advisory Committees ◽

Clinical Responses

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR707 comprises the extracellular domain of CD16 linked to a CD3ζ signaling domain and a CD28 co-stimulatory domain. ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560). Here we present clinical findings from the dose escalation phase of Study ATTCK-20-03, an ongoing, multicenter, phase 1 study of ACTR707+rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The primary objectives of this first-in-human study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Other objectives include evaluating antitumor activity and ACTR T-cell persistence. Subjects must have CD20+ NHL that is R/R after prior treatments, which must include anti-CD20 antibody-containing chemotherapy. Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707. Additional doses of rituximab are administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study includes a dose escalation phase (increasing doses of ACTR707 with fixed dose of rituximab at 375 mg/m2 q3w) and an expansion phase at the RP2D. Results: Six subjects received ACTR707 at Dose Level 1 (DL1; 23-38×106 ACTR+ T cells), 3 subjects at DL2 (30-50×106 ACTR+ T cells), and 5 subjects at DL3 (45-55×106 ACTR+ T cells). The majority of the subjects were diagnosed with DLBCL (93%) and had refractory disease (71%), defined as progressive disease as the best response to any prior treatment or relapse <1 year post autologous stem cell transplant. In DL1 through DL3, as of 27 May 2019, there were no dose-limiting toxicities, AEs of cytokine release syndrome (CRS), serious or severe neurologic AEs, or AEs leading to deaths on treatment. TEAEs reported in >2 subjects, regardless of causality or grade, included neutropenia, thrombocytopenia, anemia, febrile neutropenia, pyrexia, cough, constipation, diarrhea, nausea, and vomiting. SAEs considered possibly related to ACTR707 were febrile neutropenia (n=2) and cytopenia (n=1). ACTR707 expansion generally reached peak levels within 1 to 2 weeks after administration. All subjects with complete response (CR) up to 1 year had detectable ACTR at the last timepoint evaluated. Higher ACTR707 CD8:CD4 T-cell ratios were associated with clinical responses. Clinical activity was reported across DL1 through DL3, with an overall response rate of 64% including durable complete responses (CRs), with one subject in CR for 387+ days (Table 1). Conclusions: Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4. Disclosures Flinn: TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; 47 Inc: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Akard:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Bachanova:Celgene: Research Funding; Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Research Funding.

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Lisocabtagene Maraleucel (liso-cel) for Treatment of Second-Line Transplant Noneligible (TNE) Relapsed/Refractory (R/R) Aggressive Non-Hodgkin Lymphoma (NHL): Initial Results from the PILOT Study

Blood ◽

10.1182/blood-2019-127658 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2882-2882 ◽

Cited By ~ 1

Author(s):

Alison R. Sehgal ◽

John Godwin ◽

John Pribble ◽

Lei Wang ◽

Jerill Thorpe ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Car T Cell ◽

Car T ◽

Equity Ownership ◽

Grade 3 ◽

Large B Cell

Background: Patients (pts) with R/R aggressive large B cell NHL who fail first-line therapy with immunochemotherapy and are ineligible for high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT) have a poor prognosis. Available treatment options include platinum/gemcitabine-based or bendamustine-based regimens in combination with rituximab, with or without radiotherapy, or clinical trials. However, long-term outcomes remain poor due to lack of a curative option. Liso-cel is an investigational, anti-CD19, defined composition, 4-1BB CAR T cell product administered at target doses of CD4+ and CD8+ CAR T cells. In the ongoing TRANSCEND NHL 001 study of liso-cel as third- or later-line treatment for pts with R/R large B cell NHL, preliminary data showed high overall response rates with a low incidence of grade ≥3 cytokine release syndrome (CRS) and neurological events (NEs) (Abramson et al, ASCO 2018). The open-label, phase 2 PILOT study is assessing the safety and efficacy of liso-cel as second-line therapy in TNE pts (NCT03483103). PILOT is the first study evaluating CAR T cell therapy focusing on this pt population. Methods: Eligible pts had R/R large B cell NHL (diffuse large B cell lymphoma [DLBCL], not otherwise specified [NOS], de novo or transformed indolent NHL, high-grade lymphoma with MYC and BCL2 and/or BCL6 [double/triple-hit lymphoma], or follicular lymphoma (FL) grade 3B) and had received only 1 prior line of immunochemotherapy containing an anthracycline and a CD20-targeted agent (eg, R-CHOP). Pts had to be deemed ineligible for high-dose chemotherapy followed by HSCT by meeting at least 1 of the following TNE criteria while still fulfilling the criteria for CAR T cell therapy: age ≥70 years, ECOG PS of 2, and/or impaired pulmonary (DLCO ≤60% but SaO2 ≥92% on room air and CTCAE ≤1 dyspnea), cardiac (LVEF ≥40% and <50%), renal (creatinine clearance >30 and <60 mL/min), or hepatic function (AST/ALT >2 and ≤5 ×ULN). Liso-cel was administered at a target dose of 100×106 CAR+ T cells after lymphodepletion (LD) with fludarabine/cyclophosphamide for 3 days. Pts could be treated as outpatients at the investigator's discretion. Results: At data cutoff, 10 pts had been leukapheresed, and 9 pts had LD followed by liso-cel infusion; 1 pt is awaiting liso-cel treatment. Liso-cel was manufactured successfully in all pts. Five pts were infused and monitored as outpatients. Median age was 71 (range, 64-79) years; 5 pts were male. Histology included DLBCL NOS (n=7) and transformed FL (n=2); 2 pts had triple-hit, one of whom had transformed from FL. Five pts had relapsed from, and 4 pts had disease refractory to, prior therapy. Median SPD and LDH were 26.6 cm2 and 201 U/L, respectively. Four pts had high tumor burden with SPD ≥50 cm2 (n=4) and/or LDH ≥500 U/L (n=1). The median Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score was 3 (range, 0-3). Six pts had 1 or more treatment-emergent adverse events (TEAEs) grade ≥3, which were primarily cytopenias. Three pts had prolonged grade ≥3 cytopenias at Day 29. Two pts had infections of any grade; no pts had grade ≥3 infections. No pts had CRS or NEs, and no pts received tocilizumab, corticosteroids, or vasopressors. There were no cases of macrophage activation syndrome, tumor lysis syndrome, infusion reactions, or grade 5 TEAEs. Among the 5 pts treated and monitored as outpatients, none were admitted to hospital for adverse events within the first 29 days post liso-cel infusion. All 9 pts achieved an objective response. Four pts achieved complete response; all are ongoing. Five pts achieved partial response (PR), with 2 PRs ongoing. Results were similar in inpatient vs outpatient pts. Median follow-up was 3.5 months. Median (range) time to peak CAR T cell expansion was 10 (7-21) days. Conclusions: These preliminary safety and efficacy data from the ongoing phase 2 PILOT study suggest that liso-cel can be successfully administered, including in the outpatient setting, as second-line therapy in pts with R/R aggressive B cell NHL who were ineligible for high-dose chemotherapy and HSCT by prespecified criteria. Updated safety and efficacy data with longer follow-up will be presented. Disclosures Sehgal: Kite/Gilead: Research Funding; Merck: Research Funding; Juno/Celgene: Research Funding. Pribble:Celgene/Juno: Employment. Wang:Celgene Corporation: Employment. Thorpe:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Hildebrandt:Axim Biotechnologies: Equity Ownership; Abbvie: Equity Ownership; GW Pharmaceuticals: Equity Ownership; Endocyte: Equity Ownership; Clovis Oncology: Equity Ownership; Kite Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other; CVS Health: Equity Ownership; Celgene: Equity Ownership; Axim Biotechnologies: Equity Ownership; Pharmacyclics: Research Funding; Sangamo: Equity Ownership; Cellectis: Equity Ownership; Bluebird Bio: Equity Ownership; Bristol-Myers-Squibb: Equity Ownership; crispr therapeutics: Equity Ownership; IDEXX laboratories: Equity Ownership; Johnson & Johnson: Equity Ownership; Pfizer: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Procter & Gamble: Equity Ownership; Vertex: Equity Ownership; Scotts-Miracle: Equity Ownership; Takeda: Research Funding; Bayer: Equity Ownership; Astellas: Other: Travel; Kite Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Novartis: Equity Ownership; Aetna: Equity Ownership; Juno Therapeutics: Equity Ownership; Cardinal Health: Equity Ownership; Novartis: Equity Ownership; Insys Therapeutics: Equity Ownership; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Immunomedics: Equity Ownership.

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An Interim Report on a Phase 1/2 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC ®) Targeting B Cell Maturation Antigen for the Treatment of Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-148176 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1654-1654

Author(s):

Sumit Madan ◽

Al-Ola Abdallah ◽

Andrew J. Cowan ◽

William I. Bensinger ◽

Jens Hillengass ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Phase 1 ◽

Life Extension ◽

Publicly Traded ◽

Advisory Committees ◽

Activation Markers ◽

B Cell Maturation

Abstract Background B cell maturation antigen (BCMA) is a clinically validated target for multiple myeloma (MM) based on its restricted expression profile and potential functional role in promoting MM cell survival. HPN217 is a BCMA-targeting T cell engager derived from the Harpoon Tri-specific T cell Activating Construct (TriTAC ®) platform. It is a recombinant polypeptide of approximately 50 kDa, engineered to be a small globular protein to enable efficient drug diffusion and exposure in tumor tissue and have a prolonged serum half-life at the same time. It contains three humanized antibody-derived binding domains, targeting BCMA for MM cell binding, albumin for half-life extension, and CD3ε for T cell engagement, activation, and cytolytic function differentiation. Methods The ongoing Phase 1 study initially evaluates escalating doses of once weekly IV administrations of HPN217 in patients with relapsed/refractory (R/R) MM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and a CD38-targeted therapy. Prior exposure to BCMA-targeting agent is permitted for this initial part of the trial. Premedication to minimize cytokine release syndrome (CRS) includes dexamethasone, diphenhydramine, acetaminophen, and a proton pump inhibitor. Primary endpoints are safety, tolerability, and determination of maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D). Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-myeloma activity. Results As of July 5, 2021, 22 patients have been treated with HPN217 in 8 individual cohorts ranging from 5 to 2150 µg/week. Patients treated received a median of 8 (range of 4 - 16) prior systemic regimens, including 5 patients who received prior BCMA-targeted belantamab mafodotin or orvacabtagene autoleucel. No dose-limiting toxicities (DLTs) have been observed and MTD has not been reached. The most common treatment-emergent adverse events (TEAEs) are hematological changes including anemia, neutropenia, and thrombocytopenia. No CRS was observed in dose cohorts receiving 5 - 270 µg/week (n=7). CRS (Grade 1, 2) was observed in 4 of 15 patients receiving ≥810 µg/week. In one patient treated at 810 µg/week, transient elevated liver transaminases (Grade 4 AST and Grade 3 ALT) was observed. A second patient in the 270 µg/week cohort also showed Grade 1 AST increase. All CRS events and liver enzyme increases resolved, and all patients were successfully re-treated with escalating doses. HPN217 demonstrated a dose proportional increase in Cmax and AUC with a median serum half-life of 74 hours (range of 38 - 197 hours), confirming half-life extension. Half-life, clearance rate, and volume of distribution were dose-independent, suggesting linear PK kinetics. Pharmacodynamic analysis shows a dose-dependent, transient increases in serum cytokines and chemokines (e.g., IL-6, IL-8, IL-10, TNFα). A transient reduction in circulating T lymphocytes accompanied by upregulation of the activation markers CD25 and CD69 were also observed. Patient response to treatment will be reported. Conclusions HPN217 represents a novel half-life extended BCMA-targeting T cell engager that can be safely administered to patients with R/R MM at a dose of up to 2150 µg weekly. TEAEs have been transient and manageable. Transient serum cytokine/chemokine increase, T cell margination and upregulation of T cell activation markers, indicate target engagement of BCMA on plasma cells and CD3 on T cells, respectively, supporting the proposed mechanism of action for HPN217. Dose escalation, including implementation of step dosing, with the goal of establishing an RP2D regimen, is ongoing. NCT04184050 Disclosures Madan: Sanofi: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Cowan: Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Secura Bio: Consultancy; Cellectar: Consultancy; Nektar: Research Funding; GSK: Consultancy; Harpoon: Research Funding. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Hillengass: Oncotracker: Membership on an entity's Board of Directors or advisory committees; Curio Science: Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Speakers Bureau; Adaptive: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Beijing Life Oasis Public Service Center: Speakers Bureau. Leleu: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; AbbVie: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Nath: Harpoon Therapeutics: Consultancy, Current equity holder in publicly-traded company. Sun: Harpoon Therapeutics: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months.

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Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2018-99-112572 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 556-556 ◽

Cited By ~ 29

Author(s):

Amanda M. Li ◽

George E Hucks ◽

Amanda M. Dinofia ◽

Alix E. Seif ◽

David T Teachey ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Abstract CAR T cell therapy in relapsed B-ALL can result in complete response (CR) rates of 80-90%, but relapse-free survival declines to 60% within the first 12-months due to both CD19-positive and negative relapses. CD19-positive relapses that occur during this time are largely due to early CAR T cell loss. We hypothesize that inhibiting the PD-1:PD-L1 (programmed cell death 1) checkpoint axis may decrease T cell exhaustion, thereby improving CAR T cell function and persistence. We report our single institution experience of the use of PD-1 inhibitors in patients with relapsed or refractory B lymphoblastic malignancies treated with CD19-directed CAR T cell therapy. Methods: Patients treated with CD19-directed CAR T cell therapy (murine CTL019 or humanized CTL119) at the Children's Hospital of Philadelphia who demonstrated repeated early CAR T cell loss or partial/no response to CAR T cell therapy received a PD-1 inhibitor starting no sooner than 14 days after CAR T cell infusion and after resolution of cytokine release syndrome (CRS) symptoms, with the possibility of repeated doses up to every 3 weeks. Results: Fourteen patients, ages 4-17 years, with heavily pretreated, relapsed B-ALL (n=13) or B lymphoblastic lymphoma (n=1), were treated with CD19-directed CAR T cell therapy (CTL019, n=4; or CTL119, n=10) in combination with pembrolizumab (n=13) or nivolumab (n=1). Three of 6 patients treated with CD19 CAR T cells in combination with a PD-1 inhibitor for early B cell recovery re-established B cell aplasia (a reflection of CAR T cell function) for 5-15 months, 2 of whom have persistent B cell aplasia with ongoing pembrolizumab therapy. Four patients started pembrolizumab for bulky extramedullary disease unresponsive to or relapsed after CAR T cells, with 2 partial and 2 complete responses seen. In one patient, significant CAR T cell proliferation was measured within days of starting pembrolizumab and in temporal correlation to radiographic disease response. In 4 patients who failed to achieve disease remission with initial CAR T cell infusion, no CRs were achieved with the addition of pembrolizumab, although partial responses were seen, and one patient progressed with CD19-dim/negative disease. CRS symptoms and fever typical of CAR T cell proliferative responses were observed in 3/14 patients within 2 days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1 inhibition were tolerable or reversible upon discontinuation, and including 1 case each of acute pancreatitis, hypothyroidism, arthralgias, urticaria, as well as 4 patients with grade 3-4 cytopenias. No grade 5 toxicities or graft-versus-host disease flares occurred. Two patients discontinued pembrolizumab for delayed adverse effects after multiple doses; both patients relapsed/progressed with CD19+ disease a few weeks after discontinuation. Discussion: T cell exhaustion or activation induced CAR T death (AICD) has been suspected to contribute to poor persistence of CAR T cells. We hypothesized that the PD-1 checkpoint pathway may be involved in CAR T cell exhaustion in some cases, which may be overcome by checkpoint inhibition. Here, promising responses were specifically seen in those with early B-cell recovery and bulky extramedullary disease. In contrast, PD-1 inhibition had partial, but no durable, effect in the four B-ALL patients with poor initial marrow response to CAR T cell therapy alone, suggesting a different mechanism such as AICD may be responsible for poor initial responses. No unexpected or fatal toxicities were seen. This cohort shows initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T cell therapy in children with relapsed B-ALL, and that this strategy may augment CAR T cell effect and persistence. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Callahan:Novartis Pharmaceuticals Corporation: Consultancy. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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HESTER: A Phase II Study Evaluating Efficacy and Safety of Tisagenlecleucel Reinfusion in Pediatric and Young Adult Patients with Acute Lymphoblastic Leukemia Experiencing Loss of B-Cell Aplasia

Blood ◽

10.1182/blood-2020-136340 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Michael W Boyer ◽

Sonali Chaudhury ◽

Kara L Davis ◽

Timothy Alan Driscoll ◽

Stephan A Grupp ◽

...

Keyword(s):

T Cell ◽

Young Adult ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Adult Patients ◽

Efficacy And Safety ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T

Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy approved for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma. The ELIANA trial showed efficacy (81% overall remission rate [ORR]; 60% complete remission [CR]) and safety of tisagenlecleucel in r/r B-ALL (Maude et al. N Engl J Med. 2018). In the ELIANA trial, sustained remissions were associated with B-cell aplasia, an expected on-target effect of tisagenlecleucel and a pharmacodynamic marker for tisagenlecleucel persistence. In some patients who demonstrated short CAR-T cell persistence, reinfusion with 1 or more additional doses of tisagenlecleucel has restored B-cell aplasia and produced a 60% CR rate in patients who were reinfused with humanized CD19-targeted CAR-T cell therapy (Maude et al. J Clin Oncol. 2016). This prolongs the period of tisagenlecleucel activity and immunosurveillance and may therefore prolong durable remission. We introduce a trial in progress investigating the efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with B-ALL experiencing a loss of B-cell aplasia. Study Design and Methods: HESTER (NCT04225676) is a phase II, open-label, multicenter trial to determine the efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with B-ALL experiencing loss of B-cell aplasia. Eligible patients must be ≤25 years of age with a confirmed diagnosis of CD19(+) leukemia. Patients must have been previously infused with commercial tisagenlecleucel and have at least 1 additional dose of commercial tisagenlecleucel prescribed to them in the course of medical practice. Commercial tisagenlecleucel must be given for reinfusion within 9 months of the initial manufacturing date. Patients must have loss of B-cell aplasia defined as peripheral blood (PB) absolute B lymphocyte count ≥50/μL or PB B lymphocyte ≥10% of the total lymphocytes; patients are not required to be minimal residual disease negative (MRD)(-). Karnofsky (age ≥16 years) or Lansky (age <16 years) performance status must be ≥50 at screening. Patients treated with prior gene/adoptive T-cell therapy other than tisagenlecleucel and patients with active central nervous system involvement by malignancy are excluded. The primary efficacy endpoint is the proportion of patients who reestablish B-cell aplasia within 12 months of reinfusion as measured by circulating B lymphocytes (<50/μL) and presence of tisagenlecleucel cells by quantitative polymerase chain reaction (qPCR) in the PB. Secondary outcomes include the ORR (CR + CR with incomplete blood count recovery) during the 12 months post reinfusion, event-free survival, overall survival, MRD status, and safety; immunogenicity and tisagenlecleucel persistence (by qPCR) are exploratory endpoints. Subgroup analysis of efficacy outcomes will include patients with a loss of B-cell aplasia within 9 months of first infusion who are MRD(+) at time of enrollment, as well as patients with very early (<3 mo), early (≤3 to <6 mo), and later (≥6 mo) loss of B-cell aplasia following first infusion. Safety will be assessed throughout the trial. For the primary analysis, a minimum of 10% of patients reestablishing B-cell aplasia within 12 months after reinfusion is expected with an estimated true rate of 25%. All secondary and exploratory variables will be summarized descriptively. Estimated enrollment is about 54 patients in the United States. Clinical Trial Information: NCT04225676 Disclosures Boyer: Thunder Biotech Inc: Consultancy. Grupp:Servier: Research Funding; Cellectis: Other; Roche: Consultancy; Adaptimmune: Other: SAB; Jazz: Other: SSC; TCR2: Other: SAB; GlaxoSmithKline: Consultancy; CRISPR Therapeutics/Vertex Pharmaceuticals: Other; Juno/BMS: Other; Janssen/JnJ: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Kite/Gilead: Research Funding; Allogene: Other; Novartis: Consultancy, Other: SSC, Research Funding. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Kovacs:Novartis: Current Employment. Magley:Novartis: Current Employment. Myers:Novartis: Consultancy, Honoraria, Other: ELIANA trial Steering Committee, Speakers Bureau. Phillips:Novartis: Membership on an entity's Board of Directors or advisory committees. Pulsipher:Bellicum: Honoraria; Mesoblast: Honoraria; Miltenyi: Honoraria, Research Funding; Adaptive: Research Funding; Novartis: Honoraria; Jasper: Honoraria. Purkayastha:Novartis: Current Employment. Willert:Novartis: Current Employment.

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Seroconversion Rates after COVID-19 Vaccination Amongst Patients with Hematologic Malignancies: Results of a Rapid Vaccination and Evaluation Program in a Minority Rich, Ethnically Diverse Inner City Cohort

Blood ◽

10.1182/blood-2021-151309 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2537-2537

Author(s):

Lauren C Shapiro ◽

Radhika Gali ◽

Astha Thakkar ◽

Jesus D Gonzalez-Lugo ◽

Abdul Hamid Bazarbachi ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Hematologic Malignancies ◽

Publicly Traded ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract It is well established that COVID-19 carries a higher risk of morbidity and mortality in patients (pts) with hematologic malignancies. Emerging data suggests that despite the 3 COVID-19 vaccines with emergency use authorization (EUA) by the FDA inducing high levels of immunity in the general population, pts with hematologic malignancies have lower rates of seroconversion for the SARS-CoV-2 Spike antibody (Spike IgG) and thus possibly lower protection against severe COVID-19. We established a program of rapid vaccination and evaluation of response in an inner city minority population to help determine the factors that contribute to the poor seroconversion to COVID-19 vaccination in pts with hematologic malignancies. We conducted a cross-sectional cohort study of pts with hematologic malignancies seen at Montefiore Medical Center between March 29, 2021 and July 8, 2021 who completed their vaccination series with 1 of the 3 FDA EUA COVID-19 vaccines, Moderna, Pfizer, or Johnson & Johnson (J&J). We qualitatively measured Spike IgG production in all pts using the AdviseDx Spike IgG assay and performed quantitative analysis on pts who completed their vaccination series with at least 14 days (d) after the 2 nd dose of the Moderna or Pfizer vaccines or 28d after the single J&J vaccine. Safety data was collected via questionnaires or as part of the electronic medical record. We analyzed the characteristics of these pts using standard descriptive statistics and associations between pts characteristics, cancer subtypes, treatments, and vaccine response using a Fisher Exact test, Kruskal-Wallis Rank Sum test, or Kendall Tau-b test. A total of 121 pts with hematologic malignancies were enrolled and another 10 pts were included by retrospective chart review. Five pts did not have a Spike IgG performed after consent and excluded. Ten patients had Spike IgG testing before completion of their vaccination series and excluded from quantitative analyses. A total of 116 pts were included in immunogenicity analysis and 106 pts in quantitative analysis. Baseline characteristics and representative malignancies are listed in Table 1. Seventy pts (60%) received Pfizer, 36 pts (31%) Moderna, and 10 pts (9%) J&J. Median time from vaccination completion to Spike IgG was 40d. We observed a high-rate of seropositivity (86%) with 16 pts (14%) having a negative Spike IgG. Percent positivity was not statistically significant between vaccine types (p=0.50). We observed significantly lower seroconversion rates in pts with Non-Hodgkin lymphoma (p=0.005) and pts who received: cytotoxic chemotherapy (p=0.002), IVIG (p=0.01), CAR-T cell therapy (p=0.00002), and CD20 monoclonal antibodies (Ab) (p=0.0000008) especially within 6 mo of Spike Ab evaluation (p=0.01). All pts who received anti-CD19 (Axi-cel) CAR-T therapy (0/6) were seronegative, and 1 pt that received BCMA directed CAR-T (Cilta-cel) was seropositive with no association between timing CAR-T cell infusion and seroconversion/titer. Use of BCL2 inhibitors (p=0.04), CD20 monoclonal Ab (p=0.0009), CAR-T cell therapy (p=0.01), BTK inhibitors (p=0.04), current steroid use (p=0.002), and IVIG (p=0.003) also correlated with significantly lower Ab titers with a trend toward lower Ab titers in pts on any active cancer therapy at time of vaccination (p=0.051). Immunomodulatory drugs (p=0.01) and proteasome inhibitors (p=0.01) had significantly higher seroconversion rates, and pts with history prior COVID-19 (12/106) had significantly higher Ab titers (p=0.0003). Of 47 pts who received stem cell transplant, 43 received an autologous (37 seropositive, 6 seronegative) and 4 an allogeneic transplant (3 seropositive, 1 seronegative), with no significant association with seroconversion, Ab titer, or time since transplant (greater or less than 1 year). The majority of pts, 64% and 53%, reported no adverse effects (AE) to the 1 st and 2 nd dose respectively. The most common AE were mild in severity and included sore arm, muscle aches, fatigue, and fever. No life-threatening AE were observed. Our findings indicate that vaccination is safe, effective, and well tolerated in the majority of pts with hematologic malignancies. We observed that pts receiving B-cell depleting therapies are unable to mount an effective serological response to COVID-19 vaccines and remain vulnerable to the disease. Novel immunization strategies (active or passive) are urgently needed in this population. Figure 1 Figure 1. Disclosures Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; Kymera Therapeutics: Research Funding; Guidepoint: Consultancy; GLC: Consultancy. Halmos: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mirati: Research Funding; Elevation: Research Funding; Blueprint: Research Funding; Advaxis: Research Funding; Eli-Lilly: Research Funding; TPT: Membership on an entity's Board of Directors or advisory committees; Apollomics: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees. Verma: BMS: Research Funding; GSK: Research Funding; Novartis: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; Acceleron: Consultancy; Stelexis: Current equity holder in publicly-traded company; Celgene: Consultancy; Throws Exception: Current equity holder in publicly-traded company.

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Profiling the Peripheral Blood Immune Cell Repertoire in Large-B Cell Lymphoma Patients Treated with CD19 CAR-T

Blood ◽

10.1182/blood-2021-151459 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2786-2786

Author(s):

Giulia Cheloni ◽

Eleni Kanata ◽

Dina Stroopinsky ◽

Dimitra Karagkouni ◽

Jessica J. Liegel ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Single Cell ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Cell Repertoire ◽

Advisory Committees ◽

Car T Cell ◽

Car T

Abstract Background: In Zuma-1 study, approximately 40% of patients with refractory or relapsed large B cell lymphoma (LBCL) show durable response to Axi-cel. The identification of immunologic factors predictive of therapeutic efficacy and tumor escape is a critical area of investigation. The impact of CAR T cell activation on the native T cell repertoire and lymphoma specific immunity has not been elucidated. Aim: We sought to determine the role of host immune activation in response to tumor-associated antigens and the impact of consequent epitope spreading on CAR-T mediated therapeutic efficacy. To this end, we performed longitudinal single cell immunoprofiling of peripheral blood samples from ZUMA-1 patients to capture immune cell subsets and T cell repertoire during axi-cel treatment. Methods: Single cell immunoprofiling (expression + V(D)J sequencing) was performed on PBMC samples from ZUMA-1 patients (N=32), collected at leukapheresis, 4 weeks, and 6 months post CAR-T cell infusion, to examine potential markers associated with response and resistance. scRNA-seq was performed using 10x Genomics Chromium Next GEM Single Cell 5' Kit v1.1. Full-length paired α/β TCR and BCR libraries were obtained using the Chromium Single Cell V(D)J Enrichment, Human T Cell/B cell kits following manufacturer instructions, while γ/δ TCR libraries were generated using custom primers. Results: Analysis has been completed on the pilot implementation comprising 3 patients. A total of 22,403 cells passed quality-check capturing 31 cellular populations (Figure 1a). In 2 of the 3 patients analyzed, CD8 T cells, after an initial decrease at 4 weeks post CAR T infusion, exhibited an increase at 6 months post CAR T infusion reaching higher levels than those observed prior to CAR T treatment. The third patient presented an increase of the CD8 T cell compartment at 4 weeks compared to pretreatment (Figure 1a). A similar trend was observed for CD4 T cell population, with an increase at 6 months post CAR-T to a level higher than prior to CAR T infusion (Figure 1a). On the contrary, the myeloid cell compartment depicted a gradual decrease from leukapheresis to 6 months post CAR T (Figure 1a). B cells were observed only in 1 of the 3 patients at 6 months (Figure 1a). α/β TCR, γ/δ TCR and BCR clonotypes were identified and projected on the 2-dimensional embedding (Figure 1b). Full-length paired α/β TCR at single cell level showed that some of the most abundant clonotypes at baseline continued to be prominent in post CAR T timepoints (Figure 1c). An extensive expansion of new clonotypes was observed at 6 months after infusion. Moreover, in 2 of the 3 patients, we observed that T cell clonal diversity converged at 4 weeks, and diverged in one patient at 6 months post treatment (Figure 1d). The analysis of the remaining 29 patients (87 samples) is ongoing. Conclusion: The application of single cell immunoprofiling on longitudinal samples from Axi-cel-treated LBCL patients successfully captured the changes in the cellular transcriptional landscape, cell proportions, and TCR/BCR space across the time axis in high resolution. It is anticipated that the full analysis of 32 patients can elucidate the transcriptional program in response to CAR T cell therapy. Figure 1: (A) Two-dimensional uniform manifold approximation and projection (UMAP) of all cells passing QC (n=22,403), separated per patient and timepoint. (B) T and B cell receptor clonality at single cell resolution. T and B cells with one or more clones are colored. (C) α/β clonotype frequency per timepoint for each patient. (D) T Cell receptor Shannon diversity index per timepoint for the 3 profiled patients. Dashed lines connect the different timepoints from the same patient. Figure 1 Figure 1. Disclosures Stroopinsky: The Blackstone Group: Consultancy. Bot: Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support. Mattie: Kite: Current Employment. Chou: Kite Pharma: Current Employment. Rosenblatt: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Parexel: Consultancy; Wolters Kluwer Health: Consultancy, Patents & Royalties; Bristol-Myers Squibb: Research Funding; Imaging Endpoints: Consultancy; Attivare Therapeutics: Consultancy. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy.

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