YIA19-002: Axl-RTK Inhibition Modulates T Cell Functions and Synergizes With Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies

2019 ◽  
Vol 17 (3.5) ◽  
pp. YIA19-002
Author(s):  
Saad S. Kenderian ◽  
Reona Sakemura ◽  
Nan Yang ◽  
Michelle Cox ◽  
Sutapa Sinha ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Inhibitory Receptors ◽  
B Cell Malignancies ◽  
Phase 1 Clinical Trial

Despite the remarkable outcomes of CD19-directed chimeric antigen receptor T (CART19) cell therapy in B-cell malignancies, the durable responses in diffuse large B-cell lymphoma are less than 40%, and strategies to enhance this response are desperately needed. Inhibition of AXL RTK with TP0903, a high-affinity AXL inhibitor has been found to induce robust apoptosis of malignant B cells. Here, we aimed to examine the role of AXL RTK inhibition with TP0903 on T-cell function in B-cell malignancies. First, we investigated the influence of TP0903 on CART19 cell phenotype and functions. Here, we used 41BB costimulated, lentiviral-transduced CART cells. AXL inhibition led to polarization of CART cells into a Th1 phenotype when T cells were stimulated with the CD19+ mantle cell lymphoma (MCL) cell line Jeko or with leukemic B cells isolated from patients with chronic lymphocytic leukemia (CLL), in the presence of TP0903 (Fig 1A). Exposure of activated CART cells to TP0903 also resulted in significant downregulation of inhibitory receptors on activated CART cells (Fig 1B), a reduction of conical cytokines known to be associated with the development of cytokine release syndrome (CRS) (Fig 1C). To investigate the effect of AXL RTK inhibition of CART cells with TP0903 in vivo, we established MCL xenografts through the injection of 1.0x106 of Jeko into NSG mice. A week later, mice were treated with either vehicle alone, TP0903 (20 mg/kg/day) alone, 0.5x106 of CART19 alone, or TP0903 (20mg/kg/day)+0.5x106 of CART19. Three weeks after the treatment, mice were rechallenged with 1.0x106 of Jeko. Mice treated with CART19 and TP0903 rejected the tumor challenge while mice previously treated with CART19 alone redeveloped MCL, suggesting that AXL inhibition enhanced CART cell persistence (Fig 1D). Finally, we validated our preclinical findings in correlative analyses of phase 1 clinical trial of TP0903 in patients with solid tumors (NCT02729298). Similar to our findings, there was a significant reduction in Tregs, reduction of inhibitory receptors and polarization to a Th1 phenotype. These findings will be further investigated in a planned phase 1 clinical trial of TP0903 in relapsed/refractory CLL (NCT03572634) In summary, we demonstrated for the first time that AXL inhibition polarizes T cells into a Th1 phenotype, downregulates inhibitory receptors, and synergizes with CART cells in B-cell malignancies. These findings encourage further study of TP0903 as an enhancer of T-cell immunotherapies.

scholarly journals Adoptive T-Cell Therapy with TCL1-Specific TCR for B-Cell Lymphomas

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3488-3488
Author(s):  
Jinsheng Weng ◽  
Kelsey Moriarty ◽  
Yong Pan ◽  
Man Chun John MA ◽  
Rohit Mathur ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Malignancies ◽  
Advisory Committees ◽  
T Cell Therapy

Abstract Chimeric antigen receptor (CAR)-modified T-cell therapy targeting CD19 induces high response rates in patients with relapsed or refractory B-cell lymphomas. However, about 60% of patients experience primary or secondary resistance after CD19-targeted CAR T-cell therapy and a major of cause of failure appears to be due to loss of CD19 expression on the tumor. Therefore, novel targets for adoptive T-cell therapeutic approaches are needed to further improve clinical outcome in these patients. T-cell leukemia/lymphoma antigen1 (TCL1) is an oncoprotein that is overexpressed in multiple B-cell malignancies including follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). Importantly, it has restricted expression in only a subset of B cells among normal tissues. We previously identified a TCL1-derived HLA-A2-binding epitope (TCL170-79 SLLPIMWQLY) that can be used to generate TCL1-specific CD8+ T cells from peripheral blood mononuclear cells of both HLA-A2+ normal donors and lymphoma patients. More importantly, we showed that the TCL1-specific CD8+ T cells lysed autologous primary lymphoma cells but not normal B cells (Weng et al. Blood 2012). To translate the above discovery into clinic, we cloned the T-cell receptor (TCR) alpha and beta chains from a TCL1-specific CD8+ T-cell clone and showed that this TCL1-TCR could be transduced into polyclonal donor T cells using a lentiviral system with a transduction efficiency of >40% as determined by TCL170-79 tetramer positive T cells. Furthermore, we demonstrated that the TCL1-TCR-transduced T cells recognized T2 cells pulsed with TCL170-79 peptide producing IFN- γ >8 ng/ml and IL-2 >350 ng/ml but were not reactive to control HIV-Gag peptide (IFN- γ <0.1 ng/ml and IL-2 <0.2 ng/ml). The TCL1-TCR-transduced T cells recognized TCL170-79 peptide pulsed onto T2 cells at a concentration of 1-10 nM (IL-2 >10 ng/ml) suggesting it has moderate to high avidity. Importantly, TCL1-TCR-transduced T cells lysed HLA-A2+ (up to 43% lysis of Mino and 25% lysis of Jeko-1 at 40:1 Effector:Target ratio) but not HLA-A2- lymphoma cell lines (5.5% lysis of HLA A2- Raji and 2.3% lysis of Daudi at 40:1 Effector:Target ratio). TCL1-TCR-transduced T cells were also cytotoxic to HLA-A2+ primary lymphoma tumor cells (up to 48% lysis of CLL, 43% lysis of FL, 41% lysis of DLBCL, 46% lysis of splenic marginal zone lymphoma, and 11% lysis of MCL at 40:1 Effector:Target ratio) but not normal B cells derived from the same patients. Lastly, TCL1-TCR transduced T cells showed high efficacy in in vivo models. Adoptive transfer of the TCL1-TCR-tranduced T cells significantly reduced lymphoma tumor growth and extended survival in Mino mantle cell lymphoma cell line xenograft model (48% survival in TCL1-TCR-T treated group vs. 12.5% survival in control group at 10 weeks n=7-8 mice/group; P=0.02). Collectively, our data suggest that the high expression in B-cell tumors, restricted expression in normal tissues, and presence of an immunogenic CD8 T-cell epitope, make TCL1 a target for T cell-based therapeutic approaches in multiple B-cell malignancies. Our results also demonstrate that the TCL1-specific TCR-transduced T cells may serve as a novel adoptive immunotherapy approach for the treatment of patients with various B-cell malignancies (including FL, MCL, DLBCL, CLL). Acknowledgments: This study is supported by MD Anderson Moon Shot Program and CPRIT and the National Natural Science Foundation of China Grant (No. 81570189) Disclosures Neelapu: Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

Blood ◽  
2016 ◽  
Vol 127 (4) ◽  
pp. 411-419 ◽  
Author(s):  
Harriet S. Walter ◽  
Simon A. Rule ◽  
Martin J. S. Dyer ◽  
Lionel Karlin ◽  
Ceri Jones ◽  
...  
Keyword(s):  
Clinical Trial ◽  
B Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
B Cell Malignancies ◽  
Dose Escalation Study ◽  
Phase 1 Clinical Trial ◽  
Human Dose ◽  
Key Points ◽  
Btk Inhibitor

Key Points We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059. ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.

scholarly journals Distribution of chimeric antigen receptor-modified T cells against CD19 in B-cell malignancies

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhitao Ying ◽  
Ting He ◽  
Xiaopei Wang ◽  
Wen Zheng ◽  
Ningjing Lin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Target Cells ◽  
B Cell Malignancies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Over Time

Abstract Background The unprecedented efficacy of chimeric antigen receptor T (CAR-T) cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumors. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo. Methods NALM-6, a human B-cell acute lymphoblastic leukemia (B-ALL) cell line, was used as target cells. CAR-T cells were injected into a mice model with or without target cells. Then we measured the distribution of CAR-T cells in mice. In addition, an exploratory clinical trial was conducted in 13 r/r B-cell non-Hodgkin lymphoma (B-NHL) patients, who received CAR-T cell infusion. The dynamic changes in patient blood parameters over time after infusion were detected by qPCR and flow cytometry. Results CAR-T cells still proliferated over time after being infused into the mice without target cells within 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at week 6. In the clinical trial, we found that CAR-T cells peaked at 7–21 days after infusion and lasted for 420 days in peripheral blood of patients. Simultaneously, mild side effects were observed, which could be effectively controlled within 2 months in these patients. Conclusions CAR-T cells can expand themselves with or without target cells in mice, and persist for a long time in NHL patients without serious side effects. Trial registration The registration date of the clinical trial is May 17, 2018 and the trial registration numbers is NCT03528421.

scholarly journals A Phase 1 Clinical Trial of Personalized Adoptive Cellular Therapy Targeting Myelodysplastic Syndrome (MDS) Stem Cell Neoantigens (PACTN)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4373-4373
Author(s):  
Valentina Ferrari ◽  
Tiffany N Tanaka ◽  
Alison Tarke ◽  
Hanna Fields ◽  
Luca Ferrari ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Myelodysplastic Syndrome ◽  
Ex Vivo ◽  
Phase 1 ◽  
Patient Specific ◽  
Primary Study ◽  
Disease Response ◽  
Phase 1 Clinical Trial

Abstract Background: There are few therapeutic options for higher risk patients with myelodysplastic syndrome (MDS) who fail standard therapy, and their 2-year survival rate is approximately 15%. Here we report on a recently initiated collaborative (industry-academia) first-in-human phase 1 clinical trial to assess the safety and tolerability of a novel form of adoptive T cell immunotherapy for such patients that targets patient and disease-specific, mutation-derived neoantigens. This experimental therapy is based on the concept that a) cancer is caused by somatic mutations that may generate novel immunogenic proteins (ie, neopeptides and possible neoantigens), b) that the adaptive immune system can be trained ex vivo to recognize neopeptides as neoantigens and c) that infusion of culture-expanded, neoantigen-immunized autologous T cells may be safe and therapeutically effective. Methods: This is an open-label, phase 1, 3+3 dose escalation trial with 3 cell doses (0.3, 1, and 3.0 × 107nucleated cells/kg) in cohorts of 3 patients each (see www.clinicaltrials.gov, NCT-03258359). Eligible subjects are 18 years of age or older and will have Intermediate, High, or Very High risk MDS by the revised International Prognostic Scoring System, with at least one cytopenia, and will have failed or relapsed after 6 cycles of standard hypomethylating therapy or declined such therapy, an ECOG status 0-2, and adequate organ function. Each patient's MDS-related mutations are identified and autologous T cells are immunized ex vivo with peptides corresponding to the mutated protein(s), then expanded and suitability-tested for experimental infusion (referred to as PACTN). Importantly, the T cells must demonstrate neoantigen specificity and must kill autologous MDS stem-progenitor cells prior to qualification for infusion. Each eligible subject receives a single infusion of autologous PACTN followed by intensive monitoring for adverse events (AEs) for 4 weeks and periodic monitoring for 1 year. The primary study end-point (EP) is assessment of dose-limiting toxicity (DLT) and maximum tolerated PACTN dose (MTD). Secondary EPs include disease response 1 month after PACTN infusion, overall and progression-free survival at 6 and 12 months, and assessment of the peak abundance and persistence of the infused T cells in peripheral blood. Exploratory EPs include an assessment of the effect of PACTN infusion on the allele frequencies of the targeted and non-targeted MDS mutations in blood and marrow leukocytes. Results: At this time, two subjects have been infused with PACTN in the first dose cohort. Neither subject had an infusion reaction, severe AE, or DLT after follow-up for 2-3 months, nor has a disease response occurred in these subjects. Of interest, the infused PACTN product in the first subject showed 59% clonal dominance by a single T cell receptor (TCR) clone that was present at only 0.002% in patient's blood prior to T cell immunization with neoantigen related peptides. Multiple additional expanded TCR clones were also identified in the infused PACTN product. The presence of a dominant TCR clone in the PACTN product enabled the assessment of the in vivo abundance and persistence of the clone after PACTN infusion. The dominant clone expanded between day 1 and day+4 after PACTN infusion to a peak frequency of 0.13%, representing a 64-fold expansion of this TCR compared with the pre-infusion sample of blood leukocytes, then decreased to 0.09% by day +8. The clone was also demonstrated in bone marrow on day +15 at a frequency of 0.03%, representing a 20-fold expansion of this TCR clone compared with the pre-infusion marrow sample. Similar studies on the second subject are in progress, and will be continued in future subjects as the clinical trial continues. Finally, our studies show that it has been possible to effectively immunize autologous T cells to patient-specific neoantigens in all patients studied with MDS (n=4) and also all patients with AML (n=3) studied to date. Conclusion: The early results of this clinical trial support the feasibility and safety of this novel approach to adoptive T cell mediated immunotherapy for patients with higher-risk MDS and encourages continuation of the trial in the higher dose level cohorts. Disclosures Ferrari: Persimmune, Inc.: Employment. Tarke:Persimmune, Inc.: Employment. Fields:Persimmune, Inc.: Employment. Ferrari:Persimmune, Inc.: Employment. Ni:Persimmune, Inc.: Employment. Ferrari:Persimmune, Inc.: Employment. Warner:Persimmune, Inc.: Employment. Jochelson:PersImmune, Inc.: Consultancy. Bejar:Celgene: Consultancy, Honoraria; AbbVie/Genentech: Consultancy, Honoraria; Takeda: Research Funding; Genoptix: Consultancy; Modus Outcomes: Consultancy; Foundation Medicine: Consultancy; Astex/Otsuka: Consultancy, Honoraria. Vitiello:Persimmune, Inc.: Employment. Lane:PersImmune, Inc.: Employment.

scholarly journals PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report

2021 ◽  
Vol 12 ◽  
Author(s):  
Chenggong Li ◽  
Yan Sun ◽  
Jing Wang ◽  
Lu Tang ◽  
Huiwen Jiang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Complete Remission ◽  
Cell Therapy ◽  
Maintenance Therapy ◽  
B Cell ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy

MYC/BCL2/BCL6 triple-hit lymphoma (THL) is an uncommon subset of high-grade B-cell lymphoma with aggressive clinical behavior and poor prognosis. TP53 mutation is an independently poor progonistic indicator in patients with THL, hence novel therapeutic strategies are needed for these patients. CD19-directed chimeric antigen receptor(CAR19)-T cell therapy has shown promising efficacy for relapsed/refractory diffuse large B cell lymphoma (RR DLBCL), but the majority of CAR19-T cell products to date have been manufactured using viral vectors. PiggyBac transposon system, with an inclination to memory T cells, offers a more convenient and economical alternative for transgene delivery. We herein report the first case of triple-hit RR DLBCL with TP53 mutation who was treated with piggyBac-generated CAR19-T cells and accompanied by grade 2 cytokine release syndrome. The patient obtained a complete remission (CR) in the 2nd month post-infusion and demanded maintenance therapy. Whether maintenance therapy is favorable and how to administrate it after CAR-T cell infusion remain controversial. Preclinical studies demonstrated that lenalidomide could enhance antitumor activity of CAR19-T cells. Therefore, we pioneered oral lenalidomide after CAR19-T therapy in the patient from the 4th month, and he discontinued after one cycle due to side effects. The patient has still kept sustained CR for over 24 months. Our case have firstly demonstrated the feasibility, preliminary safety and efficacy of piggyBac-produced CAR19-T cell therapy in triple-hit lymphoma. The innovative combination with lenalidomide warrants further investigation. Our findings shed new light on the possible solutions to improve short-term relapse after CAR19-T cell therapy in RR DLBCL. ChiCTR, number ChiCTR1800018111.

scholarly journals ZUMA-11: A Phase 1/2 Multicenter Study of Axicabtagene Ciloleucel (Axi-Cel) + Utomilumab Patients with Refractory Large B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4084-4084 ◽  
Author(s):  
Ran Reshef ◽  
David B. Miklos ◽  
John M. Timmerman ◽  
Caron A. Jacobson ◽  
Nabila N. Bennani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Car T Cells ◽  
Car T

Background: Relapsed/refractory (R/R) large B cell lymphoma (LBCL) is associated with poor outcomes to standard salvage therapy (Crump M, et al. Blood. 2017). In SCHOLAR-1, a large multicenter, patient-level, retrospective study, patients with R/R diffuse LBCL had a 26% objective response rate (ORR) to the next line of therapy, a 7% complete response (CR) rate, and a median overall survival of 6.3 months (Crump M, et al. Blood 2017). Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for patients with R/R LBCL with ≥ 2 prior systemic therapies. With a median follow-up of 27.1 months in ZUMA-1, the ORR with axi-cel was 83% (58% CR rate) in patients with refractory LBCL (Locke FL, et al. Lancet Oncol. 2019). Activation of the costimulatory receptor 4-1BB (CD137) on CAR T cells may enhance axi-cel antitumor activity by enhancing T cell proliferation, function, and survival. Utomilumab (uto), an investigational monoclonal antibody agonist of the 4-1BB pathway, enhanced T cell function and survival in preclinical studies (Fisher TS, et al. Cancer Immunol Immunother. 2012) and had favorable single-agent safety in patients (Segal NH, et al. Clin Cancer Res. 2018). Possible mechanisms of resistance to axi-cel are thought to be suboptimal CAR T cell expansion an exclusionary tumor microenvironment and CD19 target antigen loss (Neelapu SS, et al. Blood 2017, Rossi JM, et al J Immunother Cancer. 2018). Combination strategies that increase proliferation, expansion, and persistence of CAR T cells or prevent activation-induced cell death of CAR T cells may improve clinical outcomes observed with axi-cel. ZUMA-11 is a Phase 1/2 study investigating the efficacy and safety of axi-cel + uto in patients with refractory LBCL. Methods: The primary objectives of this study are to determine the safety, recommended Phase 2 dosing and timing (Phase 1), and efficacy (Phase 2) of axi-cel + uto in adult patients with refractory LBCL. Patients with progressive or stable disease as the best response to second-line chemotherapy or relapse ≤ 12 months after autologous stem cell transplantation, a prior anti-CD20 antibody and anthracycline-containing regimen, and Eastern Cooperative Oncology Group performance status 0-1 are eligible. Patients with histologically proven primary mediastinal B cell lymphoma, history of Richter's transformation or chronic lymphocytic lymphoma, prior CAR T cell therapy, or central nervous system involvement of lymphoma are ineligible. In Phase 1, ≈24 patients in ≤ 3 cohorts will receive a single dose of axi-cel and escalating doses of uto (10, 30, or 100 mg) using a 3 + 3 design in up to 4 of 6 cohorts. The recommended uto dose will be based on dose-limiting toxicities and other factors. Patients will be leukapheresed and may receive optional, nonchemotherapy bridging therapy per investigator decision. After conditioning chemotherapy, patients will receive a single infusion of axi-cel (target dose, 2 × 106 CAR T cells/kg) on Day 0 followed by uto on Day 1 and every 4 weeks for 6 months or until progressive disease. Patients will be treated one at a time during Phase 1, and patients treated with axi-cel will be staggered by ≥ 2 weeks. Day 21 uto administration will be explored if toxicity is unacceptable with Day 1 administration. The primary endpoints are incidence of dose-limiting toxicities in Phase 1 and CR rate in Phase 2. Secondary endpoints include ORR, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells and cytokines in blood. This study uses a single-arm design to estimate the true CR rate; with a sample size of 27 patients, of which ≤ 3 patients will have been treated in the Phase 1 portion, the maximum half-width of the 95% confidence interval about response will be ≥ 21%. ZUMA-11 is open and accruing patients. Disclosures Reshef: Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Incyte: Consultancy, Research Funding; Shire: Research Funding; BMS: Consultancy; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding. Miklos:Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Precision Bioscience: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Miltenyi: Consultancy, Research Funding; Becton Dickinson: Consultancy; Janssen: Consultancy; AlloGene: Consultancy; Novartis: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Celgene-Juno: Consultancy. Timmerman:Spectrum Pharmaceuticals: Research Funding; Kite, A Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; ImmunGene: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: travel support, Research Funding. Jacobson:Novartis: Consultancy, Honoraria, Other: travel support; Bayer: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Celgene: Consultancy, Other: travel support; Pfizer: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Bennani:Kite, A Gilead Company: Consultancy, Research Funding. Rossi:Kite, A Gilead Company: Employment. Sherman:Kite, A Gilead Company: Employment. Sun:Kite, A Gilead Company: Employment. Palluconi:Kite, A Gilead Company: Employment. Kim:Kite, A Gilead Company: Employment. Jain:Kite/Gilead: Consultancy.

scholarly journals Low Levels of Neurologic Toxicity with Retained Anti-Lymphoma Activity in a Phase I Clinical Trial of T Cells Expressing a Novel Anti-CD19 CAR

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 697-697 ◽  
Author(s):  
Jennifer Brudno ◽  
Steven Hartman ◽  
Norris Lam ◽  
David F. Stroncek ◽  
John M. Rossi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Antigen Recognition ◽  
Car T Cells ◽  
Car T

Abstract Anti-CD19 chimeric antigen receptor (CAR) T cells have powerful activity against B-cell lymphoma, but improvement is clearly needed. Toxicity, including cytokine-release syndrome (CRS) and neurologic toxicity, occurs after anti-CD19 CAR T cell infusions. Most CAR T-cell toxicity is caused, either directly or indirectly, by cytokines or other proteins that are secreted from CAR T cells. The structure of a CAR is an extracellular antigen-recognition domain connected by hinge and transmembrane (TM) domains to intracellular T-cell signaling moieties. In vitro, T cells expressing CARs with hinge and TM domains from the CD8-alpha molecule released significantly lower levels of cytokines compared with T cells expressing CARs with hinge and TM domains from CD28; however, T cells expressing CARs with hinge and TM domains from CD8-alpha retained sufficient functional capability to eradicate tumors from mice (Alabanza et al. Molecular Therapy. 2017. 25(11) 2452). To reduce cytokine production with a goal of reducing clinical toxicity, we incorporated CD8-alpha hinge and TM domains into an anti-CD19 CAR. The CAR also had a human antigen-recognition domain, a CD28 costimulatory domain, and a CD3-zeta domain. This CAR was designated Hu19-CD828Z and was encoded by a lentiviral vector. Hu19-CD828Z was different from the FMC63-28Z CAR that we used in prior studies. FMC63-28Z had hinge and TM domains from CD28 along with a CD28 costimulatory domain, a CD3-zeta domain, and murine-derived antigen-recognition domains. Twenty patients with B-cell lymphoma were treated on a phase I dose-escalation clinical trial of Hu19-CD828Z T cells (Table). Patients received low-dose cyclophosphamide and fludarabine daily for 3 days on days -5 to -3. Two days later, on day 0, CAR T cells were infused. The overall response rate (ORR) after 1st treatments with Hu19-CD828Z T cells was 70%, and the complete response (CR) rate 55%; the 6-month event-free survival was 55%. The anti-lymphoma activity of Hu19-CD828Z T cells in the current trial was comparable to the anti-lymphoma activity of FMC63-28Z T cells in a similar prior trial that also enrolled patients with advanced B-cell lymphoma. In the prior trial, we observed a 73% ORR, a 55% CR rate, and a 6-month event-free survival of 64% in 22 patients treated with FMC63-28Z T cells (Kochenderfer et al. Journ. Clin. Oncology. 2017 35(16) 1803). In our previous clinical trial of FMC63-28Z T cells, the rate of Grade 3 or 4 neurologic toxicity among 22 patients treated was 55%. Strikingly, in our trial of Hu19-CD828Z T cells, the rate of Grade 3 or 4 neurologic toxicity was only 5% (1/20 patients). In addition, the rate of Grade 2 or greater neurologic toxicity with FMC63-28Z T cells was 77.3% while the rate of Grade 2 or greater neurologic toxicity with Hu19-CD828Z T cells was 15%. To explore the mechanism for the difference in neurologic toxicity in patients receiving FMC63-28Z T cells versus Hu19-CD828Z T cells, we assessed serum levels of 41 proteins in patients treated with these CAR T-cells. This comparison is valid because the same Luminex methodology was used for the serum protein analysis for both trials, and controls of known amounts of each protein were assayed to ensure that protein levels were comparable on the different trials. Lower levels of several serum proteins that might be important in CAR toxicity were found in patients treated with Hu19-CD828Z T cells versus patients treated with FMC63-28Z T cells: Granzyme A (P<0.001), Granzyme B (P<0.001), interferon gamma (P=0.011), interleukin (IL)-15 (P=0.007), IL-2 (P=0.0034), and macrophage inflammatory protein-1A (P<0.001). Median peak patient blood CAR+ cell levels were 44 cells/µL for Hu19-CD828Z and 46.5 cells/µL for FMC63-28Z (P=not significant). We hypothesize that lower levels of potentially neurotoxic proteins in patients receiving Hu19-CD828Z T cells versus FMC63-28Z T cells led to a lower frequency of neurologic toxicity in patients receiving Hu19-CD828Z T cells. The lower levels of immunologically active proteins found in the serum of patients receiving Hu19-CD828Z T cells compared with patients receiving FMC63-28Z T cells is consistent with our in vitro experiments showing lower cytokine production by T cells expressing CARs with CD8 hinge and TM domains versus CD28 hinge and TM domains. Altering CAR hinge and TM domains can affect CAR T-cell function and is a promising approach to improve the efficacy to toxicity ratio of CAR T-cells. Disclosures Rossi: KITE: Employment. Shen:Kite, a Gilead Company: Employment. Xue:Kite, a Gilead Company: Employment. Bot:KITE: Employment. Rosenberg:Kite, a Gilead Company: Research Funding. Kochenderfer:Kite a Gilead Company: Patents & Royalties: CAR technology, Research Funding; Celgene: Research Funding.

scholarly journals Salvage Therapy With Polatuzumab Vedotin, Bendamustine, and Rituximab Prior to Allogeneic Hematopoietic Transplantation in Patients With Aggressive Lymphomas Relapsing After Therapy With Chimeric Antigen Receptor T-Cells—Report on Two Cases

2021 ◽  
Vol 11 ◽  
Author(s):  
Kristin Gerhardt ◽  
Madlen Jentzsch ◽  
Thomas Georgi ◽  
Aleksandra Sretenović ◽  
Michael Cross ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Up to 60% of patients with aggressive B-cell lymphoma who receive chimeric antigen receptor (CAR) T-cell therapy experience treatment failure and subsequently have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a potentially curative approach for patients in this situation. Induction of a deep response prior to alloHSCT is crucial for long-term outcomes, but the optimal bridging strategy following relapse after CAR T-cell therapy has not yet been established. Polatuzumab vedotin, an antibody drug conjugate targeting CD79b, is a novel treatment option for use in combination with rituximab and bendamustine (Pola-BR) in relapsed or refractory disease. Patients: We report two heavily pretreated patients with primary refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) respectively who relapsed after therapy with CAR T-cells with both nodal and extranodal manifestations of the disease. After application of three courses of Pola-BR both patients achieved a complete metabolic remission. Both patients underwent alloHSCT from a human leukocyte antigen (HLA)-mismatched donor following conditioning with busulfan and fludarabine and are disease free 362 days and 195 days after alloHSCT respectively. We conclude that Pola-BR can be an effective bridging therapy before alloHSCT of patients relapsing after CAR T-cell therapy. Further studies will be necessary to define the depth and durability of remission of this salvage regimen before alloHSCT.

scholarly journals CD22 CAR Optimization for Improved in-Human Activity Following Inadequate CD22 CAR Activity in Phase 1 Clinical Trial PLAT-04

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 403-403
Author(s):  
Corinne Summers ◽  
Blake Baxter ◽  
Colleen Annesley ◽  
Jason Yokoyama ◽  
Stephanie Rhea ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Phase 1 ◽  
Chromium Release Assay ◽  
Phase 1 Clinical Trial ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Background: CD19 targeting chimeric antigen receptor (CAR) T cells have induced unprecedented remission rates in high-risk precursor B Acute Lymphoblastic Leukemia (ALL); however recurrent disease with CD19 antigen escape variants is not uncommon. Therefore, we developed a novel CD22 targeting CAR, and following preclinical validation, tested it in a first-in-human pediatric and young adult phase 1 clinical trial, PLAT-04 (NCT03244306). Four subjects were treated at 2 dose levels (DL) (1x10 6/kg (DL1) and 3x10 6/kg (DL2)). The CD22 CAR T cell product (SCRI-CAR22v1) was successfully manufactured (n=4) and no dose limiting toxicity (DLTs), cytokine release syndrome (CRS) or neurotoxicity was observed. However, all subjects had minimal CAR T cell expansion, with 3 of 4 subjects demonstrating persistent or progressive disease at day 21 evaluation despite continued CD22 expression on leukemic blasts. Based on the poor in vivo expansion and lack of activity, enrollment was voluntarily halted to interrogate and optimize the CAR construct for enhanced performance. Methods: Human T cells were transduced to express one of two CD22 CAR constructs. We designed SCRI-CAR22v2, a CD22 CAR that utilizes the same scFv as SCRI-CAR22v1 but with a shorter linker between M971 VH and VL and a shorter hinge with differing transmembrane region, and both using CD8 alpha (Figure A). This construct maintained the truncated EGFR extracellular tag (EGFRt) for tracking and potential in vivo suicide mechanism. The two transduced CAR T cell products were compared preclinically by flow cytometry, chromium release assay and in an in vivo murine model to understand differing T cell activity between the CAR constructs. Additionally, SCRI-CAR22v2 is currently under investigation in a dose finding phase 1 clinical trial, PLAT-07 (NCT04571138). Results: Following use of cetuximab-APC and biotinylated anti-human Fab antibody for surface EGFRt and CAR detection, the SCRI-CAR22v1 expresses lower levels of EGFRt but similar CAR levels on the cell surface demonstrated by MFI (Figure B). Biotinylated, soluble CD22 antigen was also used to evaluate CD22 CAR receptor activity and, as measured by MFI, a higher affinity is suggested via SCRI-CAR22v2 as compared to SCRI-CAR22v1 (Figure B). K562 cells expressing low, medium or high CD22 were used to evaluate the impact of surface antigen expression on the CAR activity level. SCRI-CAR22v2 demonstrates improved targeted cell lysis at all 3 antigen quantity levels by chromium release assay (Figure C). In NSG mice inoculated with Raji tumor cells expressing ffluc, SCRI-CAR22v2 demonstrated improved survival compared to SCRI-CAR22v1 (Figure D) and clearance of Raji tumor cells (Figure E). Based on this promising preclinical data, we initiated enrollment onto PLAT-07, a phase 1 dose finding trial (2x10 5cells/kg (DL1), 5x10 5cells/kg (DL2) and 1x10 6cells/kg (DL3)) of SCRI-CAR22v2. To date, 3 subjects have been enrolled and successfully infused at DL1. All had prior CD19-CAR therapy and 2 lacked CD19 leukemic expression at the time of SCRI-CAR22v2 infusion. At the time of cell infusion, one subject had only extramedullary disease, one had MRD of &lt;1% and one subject had a larger disease burden of 30% ALL. None experienced a DLT and all were MRD negative in the bone marrow at day 28 and the subject with EMD demonstrated a complete metabolic response by PET scan. Figure F exhibits the improved expansion and engraftment of the SCRI-CAR22v2 cells as compared to SCRI-CAR22v1 DL1 (n=3) and DL2 (n=1), and higher peak levels of CD22 CAR T cells as compared to SCRI-CAR22v1 DL1 and DL2 (Figure G). Conclusions: Despite encouraging preclinical data, SCRI-CAR22v1 demonstrated poor expansion and engraftment in a Phase 1 trial. Notably, minor CAR alterations lead to encouraging in-human activity in early clinical findings. Our experience suggests a shorter linker and hinge as well as incorporation of an CD8 alpha transmembrane region improves the clinical activity of CD22 targeted CAR T cells in subjects with recurrent disease following CD19 CAR T cells. Further evaluation is needed to elucidate the critical CAR components and/or assays at the preclinical level that can best predict which CAR should be brought to the clinic for further evaluation. Figure 1 Figure 1. Disclosures Orentas: Lentigen: Patents & Royalties. Jensen: BMS: Patents & Royalties; Umoja Biopharma: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Research Funding. Gardner: Novartis: Consultancy; BMS: Patents & Royalties.

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