scholarly journals Easix Predicts Severe Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neuro-Toxicity Syndrome (ICANS) in Patients Receiving CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3861-3861
Author(s):  
Felix Korell ◽  
Olaf Penack ◽  
Michael Schmitt ◽  
Carsten Müller-Tidow ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Validation Cohort ◽  
T Cell Therapy ◽  
Training Cohort ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Background: Endothelial dysfunction underlies the two main complications of chimeric antigen receptor T (CAR-T) cell therapy, i.e. cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The purpose of this retrospective analysis was to evaluate and validate the Endothelial Activation and Stress Index (EASIX)) as predictor for CRS and ICANS in patients receiving CD19-directed CAR-T cells. Methods: In this retrospective study, the training cohort recruited 107 patients treated with CAR-T cells at the University Hospital Heidelberg (n=83) and Charité University Medicine Berlin (n=24) from Oct 1, 2018, to March 31, 2021. Patients from the validation cohort (n=93) received CAR-T cells within the ZUMA-1 trial (ClinicalTrials.gov number: NCT02348216). The training cohort included 37 and 34 patients with relapsed / refractory (r/r) large B-cell lymphoma (LBCL) treated with Axi-cel and Tisa-cel, respectively, 1 patient with acute lymphoblastic leukemia (ALL) treated with Tisa-cel, 2 patients with mantle cell lymphoma (MCL) treated with KTE-X19 on an early access program; and 5 patients with LBCL, 5 patients with MCL, 5 patients with chronic lymphocytic leukemia, 4 patients with follicular lymphoma, and 14 patients with ALL treated with the 3 rd generation CAR-T HD-CAR-1. Median age was 57 (20-81) years, 72% were male. The 93 patients of the validation cohort all had r/r LBCL and received Axi-Cel. EASIX and serum levels of endothelial stress markers (angiopoietin-2, suppressor of tumorigenicity-2, soluble thrombomodulin and interleukin-8) were measured before start of lymphodepletion (EASIX-pre), and on days 0, 3, and 7 after CAR-T infusion. Primary endpoints were severe CRS and/or ICANS (grades 3-4). Results: Of the 107 patients of the training cohort, 61 patients (58%) developed CRS grades 1-4 and 24 patients (22%) developed ICANS grades 1-4. Higher grade CRS (grade ≥ 3) was seen in 6 patients (6%) with a median onset of 4 (0-14) days, while grade ≥ 3 ICANS occurred in 11 patients (11%; median onset 8 (4-17) days). EASIX values increased continuously from lymphodepletion to day 7 after CAR-T cell application (EASIX-pre 2.0 (0.5-76.6, interquartile range (IQR) 1.2/4.1); EASIX-d0 2.0 (0.3-91.5, IQR 1.2/4.2); EASIX-d3 2.4 (0.3-69.1, IQR 1.3/4.9) and EASIX-d7 2.7 (0.4-94.0, IQR 1.4/7.5)). In the validation cohort, Grade ≥ 3 CRS was observed in 10 patients (11%) and grade ≥ 3 ICANS in 28 patients (30%). Similar to the training cohort, EASIX values rose from lymphodepletion to day 3 after CAR-T cell application (EASIX-pre 1.8 (0.3-106.1, IQR 1.0/4.7); EASIX-d0 2.0 (0.3-120.4, IQR 1.1/4.1) and EASIX-d3 2.7 (0.3-57.9, IQR 1.7/6.2). In both cohorts, all EASIX values (pre, d0, d3, d7) were significantly higher in patients who developed either grade 3-4 CRS, ICANS or both (see Figure 1 for the training cohort). EASIX predicted grade 3-4 CRS and ICANS before lymphodepleting therapy (-pre), on day 0 and on day 3 in both cohorts: AUC EASIX-pre, training cohort 0.73 (0.62-0.85, p=0.002), validation cohort 0.76 (0.66-0.87, p<0.001). An optimized cut-off for EASIX-pre (1.86) identified in the training cohort associated with an odds ratio (OR) of 5.07 (1.82-14.10), p=0.002 in the validation cohort in multivariable binary logistic regression analysis including age, gender, diagnosis and disease stage. Serum endothelial stress markers did not predict the two complications when assessed before CAR-T infusion, but diagnostic markers were strongly associated with CRS and ICANS grade 3-4 on day+7. Conclusions: EASIX-pre is a validated predictor of severe complications after CAR-T therapy and may help to tailor safety monitoring measures according to the individual patient's needs. Data on patients from the ZUMA-1 trial were provided by Kite/Gilead. Figure 1 Figure 1. Disclosures Penack: Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Honoraria; Pfizer: Honoraria; Therakos: Honoraria; Takeda: Research Funding; Incyte: Research Funding; Priothera: Consultancy; Shionogi: Consultancy; Omeros: Consultancy. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; TolerogenixX: Current holder of individual stocks in a privately-held company; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding. Müller-Tidow: Janssen: Consultancy, Research Funding; Pfizer: Research Funding; Bioline: Research Funding. Bullinger: Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astellas: Honoraria; Menarini: Consultancy; Sanofi: Honoraria; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy; Hexal: Consultancy; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Dreger: Gilead Sciences: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy; Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau.

scholarly journals Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-6
Author(s):  
Xian Zhang ◽  
Junfang Yang ◽  
Wenqian Li ◽  
Gailing Zhang ◽  
Yunchao Su ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Backgrounds As CAR T-cell therapy is a highly personalized therapy, process of generating autologous CAR-T cells for each patient is complex and can still be problematic, particularly for heavily pre-treated patients and patients with significant leukemia burden. Here, we analyzed the feasibility and efficacy in 37 patients with refractory/relapsed (R/R) B-ALL who received CAR T-cells derived from related donors. Patients and Methods From April 2017 to May 2020, 37 R/R B-ALL patients with a median age of 19 years (3-61 years), were treated with second-generation CD19 CAR-T cells derived from donors. The data was aggregated from three clinical trials (www.clinicaltrials.gov NCT03173417; NCT02546739; and www.chictr.org.cn ChiCTR-ONC-17012829). Of the 37 patients, 28 were relapsed following allogenic hematopoietic stem cell transplant (allo-HSCT) and whose lymphocytes were collected from their transplant donors (3 HLA matched sibling and 25 haploidentical). For the remaining 9 patients without prior transplant, the lymphocytes were collected from HLA identical sibling donors (n=5) or haploidentical donors (n=4) because CAR-T cells manufacture from patient samples either failed (n=5) or blasts in peripheral blood were too high (>40%) to collect quality T-cells. The median CAR-T cell dose infused was 3×105/kg (1-30×105/kg). Results For the 28 patients who relapsed after prior allo-HSCT, 27 (96.4%) achieved CR within 30 days post CAR T-cell infusion, of which 25 (89.3%) were minimal residual disease (MRD) negative. Within one month following CAR T-cell therapy, graft-versus-host disease (GVHD) occurred in 3 patients including 1 with rash and 2 with diarrhea. A total of 19 of the 28 (67.9%) patients had cytokine release syndrome (CRS), including two patients (7.1%) with Grade 3-4 CRS. Four patients had CAR T-cell related neurotoxicity including 3 with Grade 3-4 events. With a medium follow up of 103 days (1-669days), the median overall survival (OS) was 169 days (1-668 days), and the median leukemia-free survival (LFS) was 158 days (1-438 days). After CAR T-cell therapy, 15 patients bridged into a second allo-HSCT and one of 15 patients (6.7%) relapsed following transplant, and two died from infection. There were 11 patients that did not receive a second transplantation, of which three patients (27.3%) relapsed, and four parents died (one due to relapse, one from arrhythmia and two from GVHD/infection). Two patients were lost to follow-up. The remaining nine patients had no prior transplantation. At the time of T-cell collection, the median bone marrow blasts were 90% (range: 18.5%-98.5%), and the median peripheral blood blasts were 10% (range: 0-70%). CR rate within 30 days post CAR-T was 44.4% (4/9 cases). Six patients developed CRS, including four with Grade 3 CRS. Only one patient had Grade 3 neurotoxicity. No GVHD occurred following CAR T-cell therapy. Among the nine patients, five were treated with CAR T-cells derived from HLA-identical sibling donors and three of those five patients achieved CR. One patient who achieved a CR died from disseminated intravascular coagulation (DIC) on day 16. Two patients who achieved a CR bridged into allo-HSCT, including one patient who relapsed and died. One of two patients who did not response to CAR T-cell therapy died from leukemia. Four of the nine patients were treated with CAR T-cells derived from haploidentical related donors. One of the four cases achieved a CR but died from infection on day 90. The other three patients who had no response to CAR T-cell therapy died from disease progression within 3 months (7-90 days). Altogether, seven of the nine patients died with a median time of 19 days (7-505 days). Conclusions We find that manufacturing CD19+ CAR-T cells derived from donors is feasible. For patients who relapse following allo-HSCT, the transplant donor derived CAR-T cells are safe and effective with a CR rate as high as 96.4%. If a patient did not have GVHD prior to CAR T-cell therapy, the incidence of GVHD following CAR T-cell was low. Among patients without a history of transplantation, an inability to collect autologous lymphocytes signaled that the patient's condition had already reached a very advanced stage. However, CAR T-cells derived from HLA identical siblings can still be considered in our experience, no GVHD occurred in these patients. But the efficacy of CAR T-cells from haploidentical donors was very poor. Disclosures No relevant conflicts of interest to declare.

scholarly journals B-CLL Mediated Resistance to CAR T Cell Therapy Via Insufficient Activation Is CAR-Independent

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-44
Author(s):  
McKensie Collins ◽  
Weimin Kong ◽  
Inyoung Jung ◽  
Stefan M Lundh ◽  
J. Joseph Melenhorst
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Cytokine Production ◽  
Cell Function ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chronic Lymphocytic Leukemia (CLL) is a B cell malignancy that accounts for nearly 1/3rd of adult leukemia diagnoses in the Western world. Conventional chemo-immunotherapies initially control progression, but in the absence of curative options patients ultimately succumb to their disease. Chimeric Antigen Receptor (CAR) T cell therapy is potentially curative, but only 26% of CLL patients have a complete response. CLL-stimulated T cells have reduced effector functions and B-CLL cells themselves are believed to be immunosuppressive. Our work demonstrates that insufficient activation of CAR T cells by CLL cells mediates some of these effects and that the results are conserved between ROR1- and CD19-targeting CARs. Results: In this study we used an in vitro system to model the in vivo anti-tumor response in which CAR T cells serially engage with CLL cells. Multiple stimulations of CD19 or ROR1-targeting CAR T cells with primary CLL cells recapitulated many aspects of known T cell dysfunction including reduced proliferation, cytokine production, and activation. While the initial stimulation induced low level proliferation, subsequent stimulations failed to elicit additional effector functions. We further found that these functional defects were not permanent, and that CAR T cell function could be restored by switching to a stimulus with an aAPC (artificial Antigen Presenting Cell) control cell line. The aAPCs are well-characterized as potent stimulators of CAR T cell effector responses. Flow cytometry revealed that CLL-stimulated CAR T cells retained a non-activated, baseline differentiation profile, suggesting that CLL cells fail to stimulate CAR T cells rather than rendering them non-functional. One mechanism that could dampen activation is immune suppression. We assessed this at a high level by stimulating CAR T cells with CLL cells and aAPCs mixed at known ratios. However, even cultures containing 75% CLL cells stimulated proliferation and cytokine production. Extensive immune-phenotyping revealed high level expression of the IL-2 Receptor on 90% (18/20) of the B-CLL cells tested. Since cytokine sinking via IL-2 receptor expression is a well-known mechanism of regulatory T cell suppression, we hypothesized that CLL cells similarly sink IL-2, blunting T cell activation. To test this, we supplemented IL-2 into CLL/CAR T cell co-cultures and showed that this rescued proliferation but only partially restored cytokine production. In contrast to our hypothesis, analysis of cytokine production by flow cytometry showed that CLL-stimulated CAR T cells did not produce IL-2 following a 6- or 12-hour stimulus, but TNFα was expressed after 12-hours. Similarly, CAR T cell degranulation, a prerequisite for target cell lysis was triggered after CLL recognition. These data again suggested that CLL cells insufficiently stimulate CAR T cell cytokine production, but also showed that cytolytic activity against CLL cells is intact. We further proposed that CLL cells express insufficient levels of co-stimulatory and adhesion molecules to activate CAR T cells. Flow cytometry showed that most CLL cells expressed co-stimulatory and adhesion molecules at low levels; we hypothesized that up-regulating these molecules would enhance CAR T cell targeting of CLL cells. CLL cells were activated with CD40L and IL-4, which increased expression of CD54, CD58, CD80, and CD86. Stimulating CAR T cells with activated CLL cells enhanced CAR T cell proliferation and induced cell conjugate formation, indicating cell activation. Therefore, improving CLL stimulatory capacity can rescue T cell dysfunctions. To assess whether IL-2 addition and CD40 ligation were synergistic, we combined the two assays; however, we saw no additional improvement over IL-2 addition alone, suggesting that the two interventions may act upon the same pathway. Importantly, we also showed that rescue of CAR T cell function via IL-2 addition or CD40 ligation was not CAR-specific, as we observed the functional defects and subsequent rescue with both a ROR1-targeting CAR and the gold standard CD19-targeting CAR. Conclusions: Together, these data show that CAR T cell "defects" in CLL are actually insufficient activation, and improving the stimulatory capacity of CLL cells may enable better clinical responses. Further, this effect is not CAR-specific and these results may therefore be broadly applicable to multiple therapies for this disease. Disclosures Melenhorst: IASO Biotherapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Research Funding; Novartis: Other: Speaker, Research Funding; Johnson & Johnson: Consultancy, Other: Speaker; Simcere of America: Consultancy; Poseida Therapeutics: Consultancy.

scholarly journals DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality

2020 ◽  
Vol 4 (13) ◽  
pp. 3024-3033 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Martina Pennisi ◽  
Marta Garcia-Recio ◽  
Jessica R. Flynn ◽  
Aishat Afuye ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

scholarly journals Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B cell malignancies

Blood ◽  
2020 ◽  
Author(s):  
Jordan Gauthier ◽  
Evandro D. Bezerra ◽  
Alexandre V. Hirayama ◽  
Salvatore Fiorenza ◽  
Alyssa Sheih ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Severe Toxicity ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%). After CART2, CR was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before CART1 and an increase in the CART2 dose compared to CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received Cy-Flu lymphodepletion before CART1 and a higher CART2 compared to CART1 cell dose. The identification of two modifiable pre-treatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

scholarly journals Iomab with Adoptive Cellular Therapy (Iomab-ACT): A Pilot Study of 131-I Apamistamab Followed By CD19-Targeted CAR T-Cell Therapy for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4810-4810
Author(s):  
Mark B. Geyer ◽  
Briana Cadzin ◽  
Elizabeth Halton ◽  
Peter Kane ◽  
Brigitte Senechal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Research Funding ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: Autologous CD19-targeted chimeric antigen receptor-modified (CAR) T-cell therapy leads to complete responses (CR) in patients (pts) with (w/) relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL, >80% CR rate) and diffuse large B-cell lymphoma (DLBCL, ~40-55% CR rate). However, following fludarabine/cyclophosphamide (Flu/Cy) conditioning and CAR T-cell therapy w/ a CD28 costimulatory domain (e.g. 19-28z CAR T-cells), rates of grade ≥3 ICANS and grade ≥3 cytokine release syndrome (CRS) in pts w/ R/R DLBCL and morphologic R/R B-ALL exceed 30%. CRS and ICANS are associated w/ considerable morbidity, including increased length of hospitalization, and may be fatal. Host monocytes appear to be the major reservoir of cytokines driving CRS and ICANS post-CAR T-cell therapy (Giavradis et al. and Norelli et al., Nature Medicine, 2018). Circulating monocytic myeloid-derived suppressor cells (MDSCs) may also blunt efficacy of 19-28z CAR T-cells in R/R DLBCL (Jain et al., Blood, 2021). The CD45-targeted antibody radioconjugate (ARC) 131-I apamistamab is being investigated at myeloablative doses as conditioning prior to hematopoietic cell transplantation in pts w/ R/R acute myeloid leukemia. However, even at low doses (4-20 mCi), transient lymphocyte and blast reduction are observed. Preclinical studies in C57BL/6 mice demonstrate low-dose anti CD45 radioimmunotherapy (100 microCi) transiently depletes >90% lymphocytes, including CD4/CD8 T-cells, B-cells, NK cells, and T-regs, as well as splenocytes and MDSCs, w/ negligible effect on bone marrow (BM) hematopoietic stem cells (Dawicki et al., Oncotarget, 2020). We hypothesized a higher, yet nonmyeloablative dose of 131-I apamistamab may achieve more sustained, but reversible depletion of lymphocytes and other CD45 + immune cells, including monocytes thought to drive CRS/ICANS. We additionally hypothesized this approach (vs Flu/Cy) prior to CAR T-cell therapy would promote CAR T-cell expansion while reducing CSF levels of monocyte-derived cytokines (e.g. IL-1, IL-6, and IL-10), thus lowering the risk of severe ICANS (Fig 1A). Study design and methods: We are conducting a single-institution pilot study of 131-I apamistamab in lieu of Flu/Cy prior to 19-28z CAR T-cells in adults w/ R/R BALL or DLBCL (NCT04512716; Iomab-ACT); accrual is ongoing. Pts are eligible for leukapheresis if they are ≥18 years-old w/ R/R DLBCL (de novo or transformed) following ≥2 chemoimmunotherapy regimens w/ ≥1 FDG-avid measurable lesion or B-ALL following ≥1 line of multi-agent chemotherapy (R/R following induction/consolidation; prior 2 nd/3 rd gen TKI required for pts w/ Ph+ ALL) w/ ≥5% BM involvement and/or FDG-avid extramedullary disease, ECOG performance status 0-2, and w/ appropriate organ function. Active or prior CNS disease is not exclusionary. Pts previously treated w/ CD19-targeted CAR T-cell therapy are eligible as long as CD19 expression is retained. See Fig 1B/C: Post-leukapheresis, 19-28z CAR T-cells are manufactured as previously described (Park et al., NEJM, 2018). Bridging therapy is permitted at investigator discretion. Thyroid blocking is started ≥48h pre-ARC. 131-I apamistamab 75 mCi is administered 5-7 days pre-CAR T-cell infusion to achieve total absorbed marrow dose ~200 cGy w/ remaining absorbed dose <25 cGy at time of T-cell infusion. 19-28z CAR T-cells are administered as a single infusion (1x10 6/kg, B-ALL pts; 2x10 6/kg, DLBCL pts). The primary objective is to determine safety/tolerability of 131-I apamistamab 75 mCi given prior to 19-28z CAR T-cells in pts w/ R/R B-ALL/DLBCL. Secondary objectives include determining incidence/severity of ICANS and CRS, anti-tumor efficacy, and 19-28z CAR T-cell expansion/persistence. Key exploratory objectives include describing the cellular microenvironment following ARC and 19-28z CAR T-cell infusion using spectral cytometry, as well as cytokine levels in peripheral blood and CRS. The trial utilizes a 3+3 design in a single cohort. If dose-limiting toxicity (severe infusion-related reactions, treatment-resistant severe CRS/ICANS, persistent regimen-related cytopenias, among others defined in protocol) is seen in 0-1 of the first 3 pts treated, then up to 6 total (up to 3 additional) pts will be treated. We have designed this study to provide preliminary data to support further investigation of CD45-targeted ARCs prior to adoptive cellular therapy. Figure 1 Figure 1. Disclosures Geyer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Research Funding; Amgen: Research Funding. Geoghegan: Actinium Pharmaceuticals, Inc: Current Employment. Reddy: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Berger: Actinium Pharmaceuticals, Inc: Current Employment. Ludwig: Actinium Pharmaceuticals, Inc: Current Employment. Pandit-Taskar: Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Clarity Pharma: Research Funding; Illumina: Consultancy, Honoraria; ImaginAb: Consultancy, Honoraria, Research Funding; Ymabs: Research Funding; Progenics: Consultancy, Honoraria; Medimmune/Astrazeneca: Consultancy, Honoraria; Actinium Pharmaceuticals, Inc: Consultancy, Honoraria; Janssen: Research Funding; Regeneron: Research Funding. Sauter: Genmab: Consultancy; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. OffLabel Disclosure: 131-I apamistamab and 19-28z CAR T-cells are investigational agents in treatment of ALL and DLBCL

scholarly journals Single-Cell RNA Sequencing Identifies Expression Patterns Associated with Clinical Responses to Dual-Targeted CAR-T Cell Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Tyce Kearl ◽  
Ao Mei ◽  
Ryan Brown ◽  
Bryon Johnson ◽  
Dina Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Research Funding ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Clinical Responses

INTRODUCTION: Chimeric Antigen Receptor (CAR)-T cell therapy is emerging as a powerful treatment for relapsed or refractory B cell lymphomas. However, a variety of escape mechanisms prevent CAR-T cell therapy from being more uniformly effective. To better understand mechanisms of CAR-T failure among patients treated with dual-targeted CAR-T cells, we performed single-cell RNA sequencing of samples from a Phase 1 trial (NCT03019055). The clinical trial used anti-CD20, anti-CD19 CAR-T cells for the treatment of relapsed/refractory B-cell non-Hodgkin Lymphoma. Clinical responses from this study are reported independently (Shah et al. in press in Nat Med). While robust clinical responses occurred, not all patients had similar outcomes. In single-antigen specific CAR-T cells, mechanisms of resistance include antigen down-regulation, phenotype switch, or PD-1 inhibition (Song et al. Int J Mol Sci 2019). However, very little is understood about the mechanisms of failure that are specific to dual-targeted CAR-T cells. Interestingly, loss of CD19 antigen was not observed in treatment failures in the study. METHODS: De-identified patient samples were obtained as peripheral blood mononuclear cells on the day of harvest ("pre" samples), at the peak of in vivo CAR-T cell expansion which varied from day 10 to day 21 after infusion ("peak" samples), and on day 28 post-infusion ("d28" samples). The CAR-T cell infusion product was obtained on day 14 of on-site manufacturing ("product" samples). All samples were cryopreserved and single cell preparation was performed with batched samples using 10X Genomics kits. Subsequent analysis was performed in R studio using the Seurat package (Butler et al. Nat Biotech 2018) with SingleR being used to identify cell types in an unbiased manner (Aran et al. Nat Immunol 2019). RESULTS: We found that distinct T cell clusters were similarly represented in the responder and non-responder samples. The patients' clinical responses did not depend on the level of CAR expression or the percentage of CAR+ cells in the infusion product. At day 28, however, there was a considerable decrease in the percentage of CAR+ cells in the responder samples possibly due to contracture of the CAR+ T cell compartment after successful clearance of antigen-positive cells. In all samples, the CAR-T cell population shifted from a CD4+ to a CD8+ T cell predominant population after infusion. We performed differentially-expressed gene analyses (DEG) of the total and CAR-T cells. In the pre samples, genes associated with T-cell stimulation and cell-mediated cytotoxicity were highly expressed in the responder samples. Since the responders had an effective anti-tumor response, we expected these pathways to also be enriched for in the peak samples; however, this was not the case. We hypothesize that differential expression of the above genes was masked due to homeostatic expansion of the T cells following conditioning chemotherapy. Based on the DEG results, we next interrogated specific genes associated with cytotoxicity, T cell co-stimulation, and checkpoint protein inhibition. Cytotoxicity-associated genes were highly expressed among responder CD8+ T cells in the pre samples, but not in the other samples (Figure 1). Few differences were seen in specific co-stimulatory and checkpoint inhibitor genes at any timepoint in the T cell clusters. We performed gene set enrichment analyses (GSEA). Gene sets representing TCR, IFN-gamma, and PD-1 signaling were significantly increased in the pre samples of the responders but not at later time points or in the infusion products. DISCUSSION: We found a correlation between expression of genes associated with T cell stimulation and cytotoxicity in pre-treatment patient samples and subsequent response to CAR-T cell therapy. This demonstrates that the existing transcriptome of T cells prior to CAR transduction critically shapes anti-tumor responses. Further work will discover biomarkers that can be used to select patients expected to have better clinical outcomes. Figure 1 Disclosures Johnson: Miltenyi Biotec: Research Funding; Cell Vault: Research Funding. Schneider:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents & Royalties. Dropulic:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents & Royalties: CAR-T immunotherapy. Hari:BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; Incyte Corporation: Consultancy; Takeda: Consultancy. Shah:Incyte: Consultancy; Cell Vault: Research Funding; Lily: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Verastim: Consultancy; TG Therapeutics: Consultancy; Celgene: Consultancy, Honoraria; Miltenyi Biotec: Honoraria, Research Funding.

scholarly journals Combination of Anti-CD19 and Anti-CD20 Chimeric Antigen Receptor T Cells for Relapsed and Refractory Diffuse Larger B Cell Lymphoma: An Open-Label, Single-Arm, Phase Ⅰ/Ⅱ Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1590-1590 ◽  
Author(s):  
Wei Sang ◽  
Ming Shi ◽  
Jingjing Yang ◽  
Jiang Cao ◽  
Linyan Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3 ◽  
Anti Cd20

Objective Chimeric antigen receptor T (CAR-T) cells therapy demonstrated remarkable efficiency in refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). Antigen-loss potentially leads to failure after single-target CAR-T cellss therapy. Aim to evaluate the efficiency and safety of double-target CAR-T cellss therapy, we performed a phase Ⅰ/Ⅱ clinical trial of combination anti-CD19 and anti-CD20 CAR-T cellss therapy for R/R DLBCL. Methods A total of 21 patients were enrolled, and patients were monitored for treatment response, toxicity and persistence. Patients received a conditioning regimen of fludarabine and cyclophosphamide followed by infusion of anti-CD19 and anti-CD20 CAR-T cellss. Results Of the 21 patients, 17 had objective response, and the ORR was 81.0% (95% CI, 58 to 95). 11 had CR, the CR rate was 52.4% (95% CI, 26 to 70). 4 of 9 patients in completed remission at 3 months remain in remission by 6 months, the CR rate was 44.4% (95% CI, 14 to 79). The median OS was 8.1 months (95% CI, 7 to 10) and the median PFS was 5.0 months (95% CI, 2 to 8). The median duration response was 6.8 months (95% CI, 4 to 10). Cytokine release syndrome (CRS) occurred in all patients. Of the 21 patients, 15 (71.4%) had grade 1-2 CRS, 6 (28.5%) had severe (≥grade 3) CRS, and no grade 5 CRS occurred. There were 5 patients with different degrees of neurotoxicity, namely CAR-T associated encephalopathy syndrome (CRES). There were 2 cases with grade 3 or above CRES, 5 of them were self-limited, and none of them died of severe CRS or CRES. There were significant differences in peak levels of IL-6 (P=0.004)、ferritin (P=0.008) and CRP (P=0.000) secretion between CRS 1-2 and CRS 3-4 patients within one month after CAR-T cell infusion. In terms of hematological toxicity, there were 11 cases of neutropenia above grade 3 (52.4%), 6 cases of anemia (28.6%) and 6 cases of thrombocytopenia (28.6%). After 12 patients with response and 1 patient without response received CAR-T cell therapy, CD19 cell subsets all disappeared after 2 weeks. The level of serum immunoglobulin in 14 patients with response decreased progressively after 1 week of treatment with CAR-T cells, and maintained at a relatively low level. Eight patients received intravenous immunoglobulin during CAR-T cell therapy. Conclusion Anti-CD19 combined with anti-CD20 CAR-T cell is effective in the treatment of R/R DLBCL patients.2. Anti-CD19 combined with anti-CD20 CAR-T cell therapy has the occurrence of CRS, CRES and hematological toxicity, and adverse reactions could be controlled. This is the first report to our knowledge of successful treatment of combination of anti-CD19 and anti-CD20 CAR-T cellss in R/R DLBCL. Our results provide strong support for further multiple-target CAR-T cells therapy, which could potentially resolve antigen-loss related failure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Adult Patients with ALL Treated with CD62L+ T Naïve/Memory-Enriched T Cells Expressing a CD19-CAR Mediate Potent Antitumor Activity with a Low Toxicity Profile

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4016-4016 ◽  
Author(s):  
Samer K. Khaled ◽  
Suzette Blanchard ◽  
Xiuli Wang ◽  
Jamie Wagner ◽  
Araceli Naranjo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Disease Burden ◽  
Phase 1 ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Manufacturing Platform ◽  
Grade 3

Abstract Introduction: Treatment of adults with relapsed/refractory (R/R) B-ALL using CD19-targeted chimeric antigen receptor (CAR) T cells has achieved remarkable remission rates, both in pediatric and adult populations. There are multiple CAR constructs and T cell manufacturing platforms in use, and both aspects of the therapy may impact efficacy and toxicity. Park et al. report that 83% of adult patients (pts) achieve complete response (CR) to their CD19 CAR T cells with a CD28 costimulatory domain (NEJM; 3785: 449), using an unselected peripheral blood (PBMC) manufacturing platform. Unfortunately, therapy-associated toxicities in adult and pediatric ALL pts are problematic, with grade 3/4 cytokine release syndrome (CRS) ranging from 26-49 % and neurotoxicity 18-42%. Here we report preliminary data from one arm of a phase 1 clinical trial (NCT02146924) in adult pts with R/R B-ALL testing a memory-enriched T cell starting population engineered to express a CD19-specific, CD28-costimulatory CAR (CD19:28z-CAR). All pts achieved CR or CRi with a low incidence of severe cytokine release syndrome (CRS) and neurotoxicity. Unique to this study is our Tn/mem-enriched manufacturing platform, a naïve/memory T cell-enriched T cell product that is lentivirally transduced to express our CD19:28z-CAR. The manufacturing process starts with patient PBMC, depletes the CD14+ monocytes and CD25+ Tregs, and selects for CD62L+ T cells. The resultant T cell population for CAR transduction includes both the central memory and stem cell memory populations along with naïve T cells. Preclinical studies in mice had suggested that using a more uniform T cell product with a less-differentiated T cell phenotype improved antitumor activity. This Tn/mem manufacturing platform is the same as our Tcm-derived platform (Blood;127:2980) except that CD45RA depletion was omitted. Patients and Methods: This phase I study used the activity constrained for toxicity (ACT) design, an extension of the toxicity equivalence range (TEQR) design of Blanchard and Longmate (Contemp Clin Trials; 32:114), that dose escalates based on lack of activity, while constraining the dose for toxicity. The primary objectives of this study were to test the safety and activity of Tn/mem-enriched CD19:28z CAR T cells, and to determine the phase 2 recommended dose. The primary endpoints were toxicity and disease response. Sixteen pts were consented and received a lymphodepleting regimen (LDR) of 1.5-3 gm/m2 cyclophosphamide over 2-3 days and 25-30 mg/m2 fludarabine for 3 days. Three pts received LDR, but did not receive T cells due to infection or lack of CD19+ disease. Patients received a flat dose of 200 million (M) CD19:28z-CAR T cells: 11 autologous and 2 allogeneic donor products. Of the 13 that received 200 M CAR+ T cells, 2 pts were deemed ineligible for dose escalation / disease response evaluation, as 1 received <80% of the prescribed dose (100 M) and the other had CD19-negative extramedullary disease. The median age of the 13 CAR T cell treated pts was 33 years (24-72). All pts had active bone marrow (BM) disease at the time of LDR: 8 pts (62%) had high disease burden (15-91% BM blasts) and 5 had low disease burden (</= 5% BM blasts). Patients were heavily pretreated, with a median of 5 (2-6), prior regimens. Six pts received prior allogeneic transplant (HSCT), 9 had prior blinatumomab, and 1 had prior CD19 CAR T cells. Results: Toxicity: Table 1 describes the major toxicities of the 13 CAR-treated pts, stratified based on disease burden. There were no DLTs, and T-cell therapy attributed (>/=possibly) toxicities were typically mild and reversible. Eight pts had grade 2 CRS, and 2 had grade 3 CRS. Three pts had grade 2 neurotoxicity and 2 had grade 3. Response: Eleven pts were evaluable for response, with best response of 4 CRs (MRD- by flow) and 7 CRi (6 MRD-, 1 not tested). Median response duration at last contact or HSCT start was 81 days (39-286); 8 pts proceeded to HSCT (in CR or CRi) at a median of 69 days post-CAR infusion (39-103). Conclusions: Our ongoing phase 1 trial demonstrates a 100% response rate to Tn/mem-enriched CD19:28z-CAR T cell therapy in adults with relapsed/refractory (R/R) B-ALL. Although the numbers are small, the unanimous response, combined with a tolerable and reversible toxicity profile in pts with both low and high disease burden is remarkable and suggests promise for this Tn/mem manufacturing platform for CD19 and other CAR targets. Disclosures Khaled: Juno: Other: Travel Funding; Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau. Wang:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

scholarly journals A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory B-Cell Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Jae H. Park ◽  
Isabelle Riviere ◽  
Devanjan S. Sikder ◽  
Vladimir P. Bermudez ◽  
Brigitte Senechal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
High Grade ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background: Autologous CAR T cell therapy targeting the B-cell specific surface antigen CD19 has demonstrated favorable clinical responses in relapsed or refractory (R/B) B-cell lymphomas (BCL). However, despite 40-60% initial complete response (CR) rates, only a subset of patients experience durable remissions, and there is a need to further improve the efficacy of CAR therapies by preventing relapse and attaining a deeper CR. We hypothesized that the redundancy of CD28 and CD3V signaling in a CAR design incorporating all 3 CD3Vimmunoreceptor tyrosine-based activation motifs (ITAMs) might foster counterproductive T cell differentiation and exhaustion, and therefore created a new CD19 CAR construct with calibrated CAR activation potential by mutating 2 of the 3 ITAMs, termed 1XX. In systemic ALL mouse models, 19-28z1XX CAR induced effective tumor eradication at low CAR T cell doses with improved survival compared to conventional 19-28z CAR. Further preclinical studies demonstrated that the enhanced therapeutic benefit resulted from the reduced strength of activation mediated by the 19-28z1XX CAR, achieving a favorable balance of effector and memory functions, thereby enhancing persistence of functional CAR T cells and promoting effective elimination of CD19+ leukemia at lower T cell doses than needed with 19-28z CAR T cells (Feucht J et al. Nat Med 2019). To further improve the persistence of functional CAR T cells, we screened different humanized CD19-directed scFv in the context of a 19-28z1XX CAR design and proved high specificity and functionality of 19-28z1XX CARs containing a novel humanized scFv T2 - termed 19(T2)28z1XX. Study Design and Methods: This study is a single center Phase I clinical trial of 19(T2)28z1XX in patients with R/R B-cell malignancies at Memorial Sloan Kettering Cancer Center (NCT04464200). Key disease eligibility criteria include R/R diffuse large B cell lymphoma (DLBCL), high grade BCL, primary mediastinal BCL, indolent BCL and chronic lymphocytic leukemia (CLL). Patients with prior CD19 CAR therapies are eligible as long as expression of CD19 is confirmed. Key exclusion criteria include ongoing immunosuppression such as systemic GvHD therapy and active CNS disease. The study uses a 3+3 dose-escalation design to identify the maximum tolerated dose for BCL. There are 5 planned flat-dose levels. Patients will receive conditioning chemotherapy consisting of 3 days of fludarabine and cyclophosphamide followed by a single infusion of 19(T2)28z1XX CAR T cells. In the dose-escalation phase, patients with DLBCL, high grade BCL, and primary mediastinal BCL are eligible to participate. Once the recommended phase 2 dose (RP2D) is determined, the study will open to dose expansion phase with two cohorts. Cohort 1 includes DLBCL, high grade BCL and primary mediastinal BCL (i.e. same eligibility criteria as the dose-escalation phase). Cohort 2 will include patients with indolent BCL, CLL, and Richter's transformation. The dose-expansion part of the trial is designed to further characterize the safety, efficacy, and pharmacokinetics of 19(T2)28z1XX CAR in multiple indications. The primary objective of the trial is to evaluate safety and tolerability and determine the recommended Phase 2 dose of 19(T2)28z1XX. Key secondary objectives include evaluation of 19(T2)28z1XX's efficacy and cellular kinetics. Exploratory objectives include assessment of B cell aplasia, and analysis of serum cytokines. The trial has begun enrollment in August 2020. The investigators are hopeful this study will lead to development of improved CD19 CAR T cell therapy with enhanced efficacy and favorable toxicity profiles with lower infused T cell dose. Disclosures Park: AstraZeneca: Consultancy; Servier: Consultancy, Research Funding; Autolus: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Minverva: Consultancy; Artiva: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Kite: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Genentech/Roche: Research Funding; Juno Therapeutics: Research Funding; GSK: Consultancy; Intellia: Consultancy; Allogene: Consultancy. Riviere:Fate Therapeutics Inc.: Consultancy, Other: Ownership interest , Research Funding; FloDesign Sonics: Consultancy, Other: Ownership interest; Juno Therapeutics: Other: Ownership interest, Research Funding; Takeda: Research Funding; Atara: Research Funding. Palomba:Genentech: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Regeneron: Research Funding; Novartis: Honoraria; Merck: Honoraria; Celgene: Honoraria; Pharmacyclics: Honoraria. Brentjens:BMS: Research Funding; Gracell Therapeutics: Consultancy; Juno Therapeutics (a Bristol Myers Squibb company): Patents & Royalties. Sadelain:Atara: Patents & Royalties, Research Funding; Fate Therapeutics: Patents & Royalties, Research Funding; Minerva: Other: Biotechnologies , Patents & Royalties; Mnemo: Patents & Royalties; Takeda: Patents & Royalties, Research Funding. OffLabel Disclosure: Cyclophosphamide and fludarabine will be used as conditioning therapy prior to 19(T2)28z1XX CAR T cell administration.

Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2511-2511 ◽  
Author(s):  
Prasad S. Adusumilli ◽  
Marjorie Glass Zauderer ◽  
Valerie W. Rusch ◽  
Roisin O'Cearbhaill ◽  
Amy Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Metabolic Response ◽  
Dose Range ◽  
Breast Cancers ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

2511 Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 < 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.

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