Comparing CAR T-cell therapy to standard of care as a second-line therapy for B-cell non-Hodgkin lymphoma
LBA-6 tisagenlecleucel vs standard of care as second-line therapy of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma: Analysis of the phase III BELINDA study
Michael R. Bishop, MD, (The David and Etta Jonas Center for Cellular Therapy, University of Chicago) reported results from BELINDA, a phase 3 global study comparing tisagenlecleucel (tisa-cel), a CD19-targeting autologous chimeric antigen receptor (CAR) T-cell therapy, to the standard of care for second-line treatment for patients with reduced/refractory aggressive B-cell non-Hodgkin lymphomas (R/R aNHL). Primary outcome was event-free survival at 12 weeks as defined by progressive disease or stable disease at 12 weeks or death at any time. Patients in Arm A (n=162) received optional bridging therapy followed by lymphodepletion followed by a single tisa-cel infusion. Patients in Arm B (n = 160) received platinum-based chemotherapy (PCT) of the investigator’s choice. There was an imbalance in patients with high grade B-cell lymphoma and IPI>=2 being represented more in Arm A. Patients in Arm B who responded to PCT received autologous hematopoietic cell transplantation (aHCT), and patients not responding to treatment received a second round of PCT. 50% of patients in Arm B went on to receive tisa-cel. At the 12-week follow-up, 96% of patients in Arm A had received tisa-cel, and 33% of patients in Arm B had received aHCT. Median time to infusion was 52 days for tisa-cel, 41 days in US and 57 days in non-US population. ORR for Arm A was 46%, compared to 43% for Arm B. Median EFS for Arms A and B not significantly different (3 months). Incidence of adverse effects was similar between the two arms. Adverse effects of grade 3 or higher were observed in 84% of patients in Arm A, compared to 90% in Arm B. 32% and 28% of patients in Arms A and B died in the study, and the most common cause of death in both arms was progressive disease. Further investigation indicated that disease burden of a patient prior to infusion affected outcomes: patients with progressive disease were more likely to exhibit worse outcomes. 26% and 14% of patients in Arm A and Arm B, respectively, exhibited progressive disease. The extended time period from bridging to infusion in Arm A further confounded the study. The findings from the BELINDA study underscore the importance of preventing progressive disease prior to T cell infusion and minimizing the time to infusion to improve patient outcomes. Insights gained from this study can guide future clinical trials and optimize use of CAR-T cells in patients with R/R aNHL.
CD19-targeted T-cell therapy as a second line treatment of large B cell lymphoma
(2) Primary analysis of ZUMA‑7: A phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard‑of‑care therapy in patients with relapsed/refractory large B-cell lymphoma
Frederick L. Locke, MD (Moffitt Cancer Center) reported analyses from ZUMA-7, a phase 3 trial comparing axi-cel, an anti CD19 CAR-T cell therapy, to the current standard of care (SOC) as a second-line treatment of relapsed/refractory large B cell lymphoma (R/R LBCL). 359 patients participated in the study. Patients in the axi-cel arm (n = 180) received a single infusion of 2 x 106 CAR-T cells/kg after three days of conditioning with cyclophosphade and fludarabine. Patients in the axi-cel arm could receive bridging treatment with corticosteroids but no chemotherapy. Patients in the SOC arm (n = 179) received 2 to 3 days of investigator-selected platinum-based chemotherapy, and patients with a partial or complete response proceeded to high-dose therapy with autologous stem cell rescue (HDT-ASCT). 94% of the patients in the axi-cel arm received CAR-T cell infusion, and 36% of patients in the SOC arm received HDT-ASCT. The median EFS for axi-cel was 8 months and 2 months for SOC. Two-year EFS estimates are 40.5% and 16.3%, respectively. ORR for the axi-cel arm was 83% vs 50% for the SOC arm. Median OS of the SOC arm was 35.1 months, and the HR for the two groups was 0.73. The axi-cel arm has not reached median OS. Adverse effects were similar between the two groups. Treatment emergent adverse effects of grade 3 or higher were observed in 91% of the axi-cel arm and 83% of the SOC arm. One treatment-related death was observed in the axi-cel arm, and three were observed in the SOC arm. Results from the ZUMA-7 study indicate that axi-cel could replace chemotherapy/HTD-ASCT as standard second-line treatment of R/R LBCL.
Targeting the G-protein coupled receptor in multiple myeloma
(827) Phase I first-in-class trial of MCARH109, a G-protein coupled receptor class C group 5 member D (GPRC5D) targeted CAR T cell therapy in patients with relapsed or refractory multiple myeloma
Sham Mailankody, MBBS (Memorial Sloan Kettering Cancer Center) reported preliminary results from a phase 1 trial investigating the efficacy and safety of MCARH109, a G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) targeted CAR-T cell in treating relapsed/refractory multiple myeloma (RRMM). The study population comprised of 17 patients, three patients had non-secretory myeloma, seven patients had extramedullary presentation, and 10 patients received BCMA-directed treatment including 8 who had received BCMA-directed CAR-T cell therapy. Patients received lymphodepletion chemotherapy for three days, followed by infusion of MCARH109. Dose escalation followed a 3+3 design, and four different doses (25 x 106, 50 x 106, 150 x 106, and 450 x 106 CAR-T cells) were evaluated. No dose limiting toxicities were observed in any patients. Cytoplasmic Release Syndrome (CRS) of grade 1 – 3 was observed in 92% of patients; only one patient exhibited grade 4 CRS. Median time to onset for CRS was one day, and median duration for CRS was three days. Neurological toxicity was observed in one patient. Grade 1 nail changes, an on-target, off-tumor effect were observed in 56% of patients. A partial response or better was observed in 11 (69%) patients; seven patient responses were categorized as Very Good, and a complete response was observed in two patients. 50% of patients were minimal residual disease negative in the bone marrow. The overall response rate (ORR) in patients who had previously received BCMA-directed therapy was 80%; ORR in patients who had received prior CAR -T cell therapy was 75%. The dose escalation studies for MCARH 109 are ongoing, and these preliminary results suggest promising efficacy in treating RRMM, specifically in patients who had relapsed after prior BCMA-directed CAR-T cell therapy.
Apheresis products as a source of T cells for treating multiple myeloma
(480) Apheresis products from patients with multiple myeloma treated with G-CSF are a suitable source of T cells for the production of BCMA-targeting CAR-T cells
Anthony M. Battram, PhD (Hospital Clínic de Barcelona, Barcelona, Spain) described a study that examined the effects of G-CSF treatment on T cell phenotype. It has been suggested that phenotypes of T cells from patients with relapsed/refractory multiple myeloma (MM) are associated with poor clinical response of chimeric antigen receptor (CAR) T cells in this group of patients, and use of G-CSF may affect T cell proliferation. The long-term goal of this study was to determine whether apheresis products obtained prior to autologous stem cell transplantation would yield T cells suitable for CAR- T cell therapy of MM. T cells were isolated from nine patients with MM before (PRE G-CSF) and after 4 days of G-CSF treatment (POST G-CSF). Patient T cell levels were high after G-CSF treatment. Fewer POST G-CSF T cells with stem cell memory were observed, but the proportion of naïve cells and other memory cells was not significantly different. There were no differences in the percentage of regulatory T cell expansion, transduction efficiency, or proliferation rates in PRE G-CSF vs POST G-CSF cells. PRE G-CSF and POST G-CSF cells exhibited no differences in granzyme B, IFN-alpha, or IL-2 production. PRE G-CSF and POST G-CSF cells were transduced with ARI2h, an anti-BCMA CAR, and the ARI2h-CAR T cells were injected into mouse models of advanced MM. PRE G-CSF and POST G-CSF ARI2h-CAR T cells survived longer in mice than untransformed T cells, and mice injected with PRE G-CSF vs POST G-CSF ARI2h-CAR T cells exhibited no differences in survival rate, suggesting that treatment with G-CSF does not affect the activity of ARI2h-CAR T cells in vivo. Results from this study support the hypothesis that ASCT apheresis products may be a suitable source of T cells for anti-BCMA CAR-T cell therapies.
Expression of CCR4 improves homing of CDC30-CAR-T cells to tumors
(742) CD30-directed CAR-T Cells co-expressing CCR4 in relapsed/refractory Hodgkin lymphoma and CD30+ cutaneous T cell lymphoma
Natalie Grover, MD (University of North Carolina) presented preliminary data from a phase 1 clinical trial comparing the efficacy and safety of CD30-directed CAR-T cells co-expressing the CCL17 receptor CCL4 (CCL4.CD30.CAR-Ts) to CD30.T cells that do not express CCL4 in treating patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) and CD30-positive cutaneous T cell lymphomas (CTCL). 14 patients participated in the study. Follow-up data were provided for 13 patients (11 patients with HL and two patients with CTCL). All patients had received prior CD30-directed brentuximab-vedotin. No patients exhibited severe cytokine release syndrome (CRS); two patients exhibited grade 2 CRS and one exhibited grade 1 CRS. No patients exhibited neurotoxicity / immune effector cell-associate neurotoxicity syndrome (ICANS). Of the 11 patients with HL, eight exhibited a complete response and three exhibited a partial response. Of the two patients with CTCL, one has stable disease, and the other has progressive disease. Overall response rate was 85%, with 61% complete responses. At a median follow up of 8.5 months, the median PFS for all patients was 5.2 months. The median PFS for HL patients has not been reached. One patient is in complete remission over three years post-treatment. Levels of plasma CCL17/TARC, a biomarker for treatment response, was reduced by 83% in patients two weeks post-infusion. Biopsy of one patient with HL three weeks post-infusion indicated that tumor cells were enriched for CAR-T signal compared to peripheral cells, suggesting that expression of CCR4 improves homing of CAR-T cells to tumors. These preliminary results indicate that CCL4.CD30.CAR-Ts may be a safe and effective treatment for patients with R/R HL and provide proof of concept for modifying CAR-T cells to improve localization to tumors.
Safety and efficacy of elranatamab, a BCMA-targeting bispecific molecule, in treating multiple myeloma
(895) Elranatamab (PF-06863135), a B-cell maturation antigen (BCMA) targeted CD3-engaging bispecific molecule, for patients with relapsed or refractory multiple myeloma: Results from MagnetisMM-1
Michael Sebag, MD, PhD (McGill University Health Centre) reported preliminary results from the MagnetisMM-1 phase 1 study of elranatamab, a bispecific BCMA-targeting molecule that engages CD3 on T cells, for patients with relapsed or refractory multiple myeloma (RRMM). Results from the subcutaneous cohorts were reported. Patients in Cohort 1 (dose escalation) received elranatamab at 80, 130, 215, 360, 600, and 1000 μg/kg weekly. Patients in Cohort 1.1 (monotherapy with priming) received a priming dose (600 micrograms/kg) and weekly full doses (1000 micrograms/kg) one week after priming. Patients in Cohort 2 received monotherapy with dose expansion and priming. A single priming dose of 44 mg elranatamab was followed one week later with weekly 76 mg doses of elranatamab. Premedication of dexamethasone, diphenhydramine, and acetaminophen were administered to Cohort 2 during priming and the first full dose. 55 patients received elranatamab at the most efficacious dose ( >= 215 micrograms/ kg): 20 patients were in Cohort 1, 20 patients in Cohort 1.1 and 15 patients in Cohort 2A. 27% of patients had high risk features, 91% or patients were triple class refractory and 12 patients had received prior BCMA-directed therapy. Hematologic toxicities, observed in > 1/3 of patients, were the most common side effect. Cytokine release syndrome (CRS) of grade 2 or lower was observed in 87.3% of patients. While CRS was observed in 100% of patients in Cohorts 1 and 1.1, CRS was observed in 66.7% of patients in Cohort 2. Testing of inflammatory cytokine (IFN-gamma, IL-2, TNF-alpha, IL-6) levels in patients from all three cohorts suggest elranatamab priming and pre-medication decrease acute cytokine production. Confirmed ORR was 69% at the recommended dose of 1000 g/kg, and 70% of patients with prior BCMA-directed therapy achieved response. These results support further studies of the use of elranatamab for treating patients with MM.
Patient-level matching to compare treatment regimens for large B-cell lymphoma
(183) Tafasitamab plus lenalidomide versus Pola‑BR, R2, and CAR T: Comparing outcomes from RE-MIND2, an observational, retrospective cohort study in relapsed/refractory diffuse large B-cell lymphoma
Grzegorz S. Nowakowski, MD (Mayo Clinic) described an expanded analysis of RE-MIND2, retrospective cohort analysis that compared patient outcomes from the L-MIND study, a single-arm study of tafasitamab + lenalidomide (LEN), to matched patient populations treated with NCCN/ESMO-recommended therapies for patients with relapsed/refractory diffuse large B-cell lymphoma (RR DLBCL). Patients from L-MIND were matched with patients from RE-MIND2 for six covariants: age, number of prior therapy lines, prior ASCT, history of primary refractoriness, refractoriness to the last therapy line, and Eastern Cooperative Oncology Group (ECOG) performance status. Patients from the L-MIND study had been treated with tafasitamab + LEN, and patients from RE-MIND2 had been treated with polatuzumab vedotin + bendamustine + rituximab (Pola-BR), rituximab + LEN (R2), and CD19 CAR-T therapies (CAR-T). Treatment with tafasitamab + LEN significantly improved OS compared to Pola-BR and R2. Comparing tafasitamab + LEN to CAR-T showed some OS benefit, but the improvement was not significant (22 months vs. 15 months respectively). Tafasitamab + LEN significantly increased ORR and CR compared to R2, but no difference was detected comparing tafasitamab + LEN to Pola-BR or CAR-T. Patient numbers indicate that tafasitamab + LEN may improve health outcomes for R/R DLBCL patients compared to NCCN/ESMO-recommended therapies. This study also suggests that patient-level matching may be a valuable method of comparing treatment regimens that are not in head-to-head trials.
Off-the-shelf iPSC-derived CAR natural killer cells for B-cell lymphoma
(823) Safety and efficacy of FT596, a first-in-class, multi-antigen targeted, off-the-shelf, iPSC-derived CD19 CAR NK cell therapy in relapsed/refractory B-cell lymphoma
Veronika Bachanova, MD, PhD (Masonic Cancer Center, University of Minnesota) reported results from phase 1 clinical trial investigating FT596, an induced pluripotent stem cell (iPSC)-derived, off-the-shelf, CD19-directed chimeric antibody (CAR) natural killer (NK) cell therapy in patients with relapsed/refractory B-cell lymphomas (R/R BCLs) and chronic lymphocytic leukemia. FT-596 has three anti-tumor modalities: a high-affinity non-cleavable CD16 (hnCD16) Fc receptor and a CD-19-targeting CAR provide potent dual antigen targeting against malignant B-cells, and the IL-15 receptor promotes cytokine persistence. 25 patients with R/R BCL were treated with FT596. Dose escalation of FT596 occurred by 3+3 escalation, and doses ranged from 3 x 107 cells to 9 x 108 cells. Patients in Regimen A (n=12) were treated with FT596 as monotherapy, and patients in Regimen B (n=13) were treated with FT596 combined with rituximab or obinutuzumab. Prior CAR-T use was allowed, and CD-19 expression was required for patients receiving monotherapy. No cytokine release syndrome (CRS) of grade 3 or higher, graft versus host disease, or ICANS were reported in patients from either regimen. Three instances of cytokine release syndrome (CRS; Grade ≤ 2) were reported. Most reported events were hematologic toxicities. The objective response rate was 72% at 9 x 108 cell dose. 44% of responding patients were in complete remission. For the 11 patients re-treated with a second single dose of FT596, treatment was well-tolerated, and clinical activity was maintained. 56% of patients who received ≥ 90 million FT596 cells remain in response at between 1.9 and 10.8 months from initial treatment. The data presented suggest FT596 can provide clinical benefits in patients with R/R BCL as monotherapy and in combination with chemotherapy. Further studies of dose escalation and multiple cycle treatments with FT596 are in progress.
Safety and efficacy of CD33-targeting UltraCAR-T cells for acute myeloid leukemia
(825) Phase 1/1b safety study of Prgn-3006 UltraCAR-T in patients with relapsed or refractory CD33-positive acute myeloid leukemia and higher risk myelodysplastic syndromes
David A. Sallman, MD (H. Lee Moffitt Cancer Center & Research Institute) presented results from a Phase 1 / 1b study of PRGN-3006 UltraCAR-T cells for relapsed/refractory acute myeloid leukemia and hypomethylating agent (HMA) higher risk myelodysplastic syndrome (MDS). PRGN-3006 uses a non-viral system to simultaneously express CD33 CAR, membrane bound IL-15 and a kill switch. CD33 is overexpressed on AML blasts and leukemic stem cells. 15 R/R AML patients were treated, and time from leukapheresis to infusion was 2 days. Patients in Cohort 1 (n=9) were treated with PRGN-3006 without lymphodepletion, and patients in Cohort 2 (n = 6) were treated with PRGN with lymphodepletion. Dose escalation of the two cohorts occurred in parallel. Treatment was tolerated in all 15 patients, and no deaths, dose-limiting toxicities, or neurotoxicities were reported. All patients reported toxicities and 70% were Gr 1-2. 47% of patients exhibited cytokine release syndrome (CRS); one patient developed grade 3 CRS, and the remaining cases were grade 1 or 2. No objective response rate was observed in Cohort 1. In Cohort 2, 3/6 patients had an objective response. PRGN-3006 exhibited does-dependent expansion and persistence in blood and bone marrow. Cytokine profiling of responders in Cohort 2 is underway.
CD-7 targeted CAR-T cell therapy to treat mixed phenotype acute leukemia
(1741) First-in-human clinical study of a novel CD7-targeted chimeric antigen receptor (CAR)-T cell therapy for refractory/relapsed mixed phenotype acute leukemia (MPAL)
Peihua Lu, MD (Capital Medical University, Beijing, China) reported early results from a phase 1 dose-escalation clinical study investigating the safety and efficacy of chimeric antigen T-cell (CAR-T) therapy to treat CD7-positive mixed phenotype acute leukemia (MPAL). Five patients received CAR-T therapy. Four patients had MPAL, and one patient had acute myeloid leukemia (AML). One patient received a low dose (1.5 x 105 cells/kg), three patients received the medium dose (5.0 x 105 cell/kg), and one patient received the high dose (1.0 x 106 cells/kg). All patients received bridging lymphodepleting chemotherapy of fludarabine + cyclophosphamide prior to CAR-T infusion. At a median follow-up time of 127 days, four of the five patients achieved complete remission (CR) or CR with incomplete blood recovery (CRi) in bone marrow and all achieved minimal residual disease (MRD)-negative CR. One patient with extramedullary disease did not have a response. All four patients exhibited leukemia-free survival post 133.5 days. Cytokine release syndrome (CRS) was observed in all five patients (four patients exhibited grades 1 or 2 CRS and one exhibited grade 3 CRS), and no neurotoxicity was observed. One patient with prior allogeneic stem cell transplantation developed grade 1 graft versus host disease (GVDH) after CAR-T therapy. CAR-T proliferation was verified by qPCR and flow cytometry, and the median proliferation peak occurred around Day 21 after infusion. Although more patient data are required, the safety of CAR-T therapy in treating MPAL appears manageable, and CD7-targeted CAR-T therapy may offer an opportunity for complete remission for CD7-positive patients with MPAL.
IL-1 receptor antagonist prevents CRS and neurotoxicity associated with CD 19 CAR T cell therapy
(96) A phase II study of prophylactic anakinra to prevent CRS and neurotoxicity in patients receiving CD19 CAR T cell therapy for relapsed or refractory lymphoma
Jae H. Park, MD (Memorial Sloan Kettering Cancer Center) described results from one cohort of a phase 2 study investigating the systematic use of IL-1 receptor inhibitor, anakinra (SOBI), to prevent cytokine release syndrome (CRS) and immune effector cell-associate neurotoxicity syndrome (ICANS) in patients receiving CD19 CAR T cell therapy. Patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) or mantle cell lymphoma (MCL) received anakinra 100 mg subcutaneously every 12 hours on day 2 of T cell infusion or earlier (two consecutive temperatures ≥ 38.5°) and continued until at least day 10. Anakinra use could be extended for persistent CRS beyond day 10. Tocilizumab and or corticosteroids were administered to patients exhibiting persistent or worsening CRS and neurotoxicity. The study population was comprised of 31 patients: 74% received axicabtagene ciloleucel, 13% received tisagenlecleucel, 13% received brexucabtagene autoleucel. CRS of all grades was observed in 74% of patients, with severe CRS (Grade 3 or higher) in 6% of patients. ICANS of all grades was observed in 19% of patients, with severe ICANS (Grade 3 or higher) in 9.7% of patients. 13% of patients required a transfer to the ICU. Use of tocilizumab and/or corticosteroids was lower than previously published studies, at 29% and 19%, respectively. Overall response rate for all patients was 78%, with 68% complete response rate. Overall response rate for patients with LBCL was 74% and 100% for patients with MCL. This study validates previous findings that IL-1 is an important target for prevention of severe CRS and ICANS in patients receiving CD19 CAR T cell therapy and suggests that early treatment with anakinra is a safe and feasible approach to prevent severe CRS and all grades of ICANS in patients receiving CD19 CAR T cell therapy.