ASH 2018 Meeting Highlights - Dec. 3

Highlights from Dec. 3, 2018

Checkpoint inhibition after CAR T therapy is safe and may extend CAR T persistence

Amanda Li, MD (Children’s Hospital of Philadelphia, Philadelphia, Penn., USA), discussed institutional results concerning the safety and efficacy of anti-PD-1 checkpoint inhibitors in patients with B cell malignancies who have received prior anti-CD19 CAR T therapy. This retrospective analysis included 14 patients (median age = 9.5 [4-17], heavily pretreated, relapsed/refractory B cell acute lymphoblastic leukemia = 13, B cell lymphoma = one) who received anti-PD-1 checkpoint inhibitors (pembrolizumab = 13 [10mg/kg = 10, 2mg/kg = one]; nivolumab = one [3mg/kg]) no sooner than two weeks after anti-CD19 CAR T therapy. At median follow up of 13.3 months (2.3 – 44.6) the overall response rate (ORR) in these patients was 50 percent (n = seven), with four patients achieving a complete response (CR) and two achieving a partial response (PR). While checkpoint inhibitors provided little benefit to four patients with partial or no response to CAR T therapy, data suggest that they were able to extend CAR T persistence in patients with early B cell recovery after reinfusion. Responses were also observed in patients with bulky disease. The majority of the observed adverse events included grade 3/4 neturopenia (n = four) and thrombocytopenia (n = three). Interestingly, only one patient experienced cytokine release syndrome (grade two) that was resolved with tocilizumab. Together, these data suggest that checkpoint inhibition is safe in patients with hematologic malignancies treated with anti-CD19 CAR T therapy, and that anti-PD-1 agents may be able to help extend CAR T cell persistence.

Introduction of a CD8-alpha hinge and transmembrane domains into anti-CD19 CAR T cells increases safety while retaining anti-tumor efficacy

James Kochenderfer, MD (National Cancer Institute, Bethesda, Md., USA), presented phase 1 clinical trial data evaluating the use of the novel anti-CD19 CAR T therapy Hu19-CD828Z for the treatment of patients with B cell lymphoma. Pre-clinical data suggest that incorporation of CD8-alpha hinge and transmembrane domains into anti-CD19 CARs containing a CD28 costimulatory domain helped reduce cytokine secretion – potentially alleviating toxicities - while retaining sufficient anti-tumor activity. As such, 20 patients with pre-treated B cell lymphoma (> one prior therapy, diffuse large B cell lymphoma [DLBCL] = 14, follicular = three, Mantle cell = two, Burkitt = one) received lymphodepleting chemotherapy (fludarabine [30mg/m2] + cyclophosphamide [300mg/m2] for three days) followed by Hu19-CD828Z infusion. ORR was 70 percent with 55 percent of patients achieving CR, and six-month event-free survival was 55 percent. These data are similar to previously reported findings from 22 patients with advanced B cell lymphoma treated with similar anti-CD19 CAR T cells which lacked the CD8-alpha hinge and transmembrane domains (FMC63-28Z, n = 22, ORR = 73 percent, CR = 55 percent, six-month event-free survival [EFS] = 64 percent). Importantly, while grade 3/4 neurotoxicities were observed in 55 percent of patients treated with FMC63-28Z (12/22), only 5 percent of patients treated with Hu19-CD828Z had such events (1/20). Analyses revealed that Hu19-CD828Z cells displayed reduced secretion of IFNgamma, IL-2, TNFalpha, and IL-4 (each p = 0.03). Additionally, reduced serum concentrations of granzyme A (p < 0.0001), granzyme B (p < 0.0001), IL-15 (p = 0.007), IL-2 (p = 0.003), MCP-1 (p < 0.0001), and MIP-1alpha (p = 0.0009) were observed in patients treated with Hu19-CD828Z compared to patients treated with FMC63-28Z. Together, these data suggest early clinical activity and enhanced safety of Hu19-CD828Z compared to FMC63-28Z may be mediated in part by reduced cytokine secretion.

Phase 1b/2 clinical trial data suggest efficacy and safety of anti-CD30 CAR T cells for the treatment of patients with CD30+ hematologic malignancies

Natalie Grover, MD (University of North Carolina, Chapel Hill, N.C., USA), presented data from a phase 1b/2 clinical trial assessing efficacy and safety of anti-CD30 CAR T cell therapies for the treatment of patients with CD30+ relapsed/refractory Hodgkin/non-Hodgkin lymphomas. In all, 24 patients (median age = 34.5 years [23-69], median prior therapies  = 7.5, Hodgkin = 22, enteropathy associated T cell lymphoma = one, Sezary syndrome = one) recieved lymphodepleting chemotherapy (first eight patients = two days bendamustine [90mg/m2], remaining 16 patients = three days bendamustine [70mg/m2] + fludarabine [30mg/m2]) before receiving either 1 x 108 (DL1) or 2 x 108 CAR T cells (DL2). Concerning patients who received bendamustine-only lymphodepletion, only 3/8 patients in the DL2 cohort achieved CR, all three of which were in CR prior to lymphodepletion. In contrast, 12/16 DL2 patients who received bendamustine / fludarabine lymphodepletion achieved CR (75 percent). At median follow-up of 100 days, median progression free survival (PFS) was also increased in patients who received DL2 and bendamustine/fludarabine lymphodepletion compared to patients who were treated at DL1 and DL2 who received lymphodepletion with single agent bendamustine (Median PFS = 396 vs 55 days, respectively, p = 0.001). Analyses revealed decreased IL-15 and IL-7 in patients treated with bendamustine monotherapy that may explain the observed efficacy differences across lymphodepleting regimens. Across both cohorts, no neurotoxicities were observed. Three patients total developed CRS (grade one = two, grade two = one). In summary, these early data suggest that anti-CD30 CAR T cells are well tolerated and may be effective in patients with CD30+ lymphomas when coupled with pretreatment bendamustine/fludarabine lymphodepletion.

Updated LEGEND-2 data suggest safety and efficacy of treatment of patients with multiple myeloma with anti-BCMA CAR T therapy LCAR-B38M

Wan-Hong Zhao MD, PhD (The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, ShaanXi, China), discussed updated results from the Phase 1 LEGEND-2 clinical trial (NCT03090659) evaluating safety and efficacy of the anti-B cell maturation antigen (BCMA) CAR T cell therapy LCAR-B38M for the treatment of patients with relapsed/refractory multiple myeloma. In all, 57 patients (median age = 54 [27-72], median prior therapies = three [1-9]) from a single institution (Xi’an) received LCAR-B38M CAR T cells (median CAR+ cell dose = 0.5x106 cells/kg, [0.07–2x106] over three infusions (20% d1, 30% d3, and 50% d7 of total dose) after three doses of cyclophosphamide lymphodepletion (300mg/m2 on days -5,-4, and -3). At median follow-up of 12 months (0.7-25.1), CRS was observed in 90 percent of patients (n = 51, grade one = 24, grade two = 20, grade three =  four). Only one grade one neurotoxicity was noted. One death occurred each due to esophagitis, pulmonary embolism, and acute coronary syndrome. ORR was 88 percent (95 percent CI: 76 – 95), with 42 patients achieving CR (74 percent, 95 percent CI: 60 – 85). 39/42 (68 percent) patients with CR were minimal residual disease (MRD)-negative confirmed via flow cytometry. Median PFS in all patients was 15 months (95% percent CI: 11 – NR) and 24 months for patients with MRD-negative CR (95 percent CI: 15 – NR). Median duration of response was 16 months (95 percent CI: 12 – NR). Median overall survival was not yet reached for both the overall cohort as well as in patients with MRD-negative CR. Together, these data suggest both efficacy and manageable safety of LCAR-B38M CAR T cells for the treatment of patients with relapsed/refractory multiple myeloma. A Phase 1b/2 study is ongoing.

Early clinical trial data suggest allogeneic UCART19 may be a safe and effective treatment option for patients with acute lymphoblastic leukemia

Reuben Benjamin, MBBS, PhD (King's College London, London, United Kingdom), presented preliminary safety, kinetic, and efficacy data of UCART19 – an allogeneic, CD52-, TRAC-, allogeneic anti-CD19 CAR T cell therapy that can be administered in non-HLA matched individuals – for the treatment of patients with CD19+ relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). 20 patients enrolled in the CALM study (median age 29.5 [18-62], n = 14) and PALL study (median age 2.7 [0.8-16.4], n = seven) received UCART19 (CALM = 1x105 cells/kg [DL1], 1x106 cells/kg [DL2], or 3x106 cells/kg [DL3]; PALL = 1.1 – 2.3x106 cells/kg) after lymphodepletion (cyclophosphamide: CALM =1500 mg/m2, PALL = 120 mg/kg; fludarabine: CALM = 90 mg/m2, PALL = 150 mg/m2) with or without alemtuzumab (1 mg/kg or 40mg). CRS was observed in 19/21 evaluable patients (90.5 percent; grade one = four, grade two = 12, grade three = two). One patient died in the context of grade four CRS and neutropenic sepsis. Neurotoxicities were observed in 8/21 patients (38.1 percent), all of which were grade 1/2. Two patients developed reversible grade 1 graft vs host disease. 14/21 evaluable patients (67 percent) achieved CR, all of which had received alemtuzumab during lymphodepletion. 10/14 patients who achieved CR (71 percent) were MRD-negative. Alternatively, all four patients who did not receive alemtuzumab had progressive disease. Interestingly, UCART19 expansion was observed in 15/17 patients who received alemtuzumab, but was not observed in any patients treated with fludarabine + cyclophosphamide only. In all, these early data suggest that UCART19 is well tolerated and an effective treatment option for patients with B-ALL.

Early data reveal significant response in pediatric acute lymphoblastic leukemia patients treated with a novel bispecific anti-CD19/CD22 CAR T therapy

Liora Schultz, MD (Stanford University, Palo Alto, Calif., USA), presented early Phase 1 clinical trial data assessing safety and efficacy of treatment of patients with B-ALL using a novel CD19/CD22 bispecific CAR T therapy. Pre-clinical data suggest that CD19/CD22 bispecific CAR T cells had cytotoxicity against both CD19+/CD22- and CD19-/CD22+ tumors. Based on these data, four pediatric patients (2-17) received initial lymphodepleting chemotherapy (fludarabine [25mg/m2 for three days] + cyclophosphamide [900mg/m2 for one day]) followed by 1x106 CAR T cells. CRS was observed in three patients (grade one = two, grade two = one), and two patients experienced grade one neurotoxicities. One DLT of prolonged, reversible aplasia was observed. All four patients achieved CR by 28 days post-infusion, and three patients were MRD-negative assessed by flow cytometry. CAR T cells were detectable by day six in all patients, with peak expansion occurring between day 6-14. CD4+ and CD8+ abundance varied between patients. Interestingly, multiparametric immune phenotyping indicate increased T-bet and PD-L1 as well as reduced CD127 in one patient who experienced CAR loss and relapsed. In summary, these early studies suggest promising safety and efficacy of anti-CD19/CD22 CAR T cell therapy for the treatment of patients with B-ALL, and provide insight into markers that correlate with therapeutic response.

Phase 1 clinical trial data suggest defined CD4+/CD8+ anti-BCMA CAR T cell therapy is a well tolerated, effective treatment option for multiple myeloma patients

Damian Green, MD (University of Washington, Seattle, Wash., USA), presented phase 1 clinical trial results evaluating safety and efficacy of a CD4+/CD8+ balanced anti-BCMA CAR T therapy for the treatment of patients with relapsed/refractory multiple myeloma. In all, 11 patients (median age = 63 [43-76], greater than or equal to 5 percent BCMA expression, median prior therapies = 11) received 5x107 (n=7) or 15x107 (n=4) CAR T cells following lymphodepleting chemotherapy (fludarabine [25mg/m2] + cyclophosphamide [300mg/m2] for three days). CAR T cells prior to infusion were formulated to include a 1:1 ratio of CD4+ and CD8+ cells (+/- 15%) to ensure consistency across infusion products for reproducibility. CRS was observed in 10/11 patients across all doses, all of which were grade 1/2 (grade one = one, grade two = nine). One neurotoxicity event was observed. No dose-limiting toxicities were noted. ORR 28 days-post infusion was 100 percent, including four CR, five VGPR, and two PR. 9/11 patients remain in remission as of data cutoff. One patient relapsed after therapy with BCMA-negative disease. Analyses reveal significant CD4+ and CD8+ CAR T cell expansion, and in one patient CAR T cells were detectable up to 90 days post-infusion. These early data indicate that CD4+/CD8+ balanced anti-BCMA CAR T therapy is well tolerated and has promising efficacy in patients with relapsed/refractory multiple myeloma. Studies investigating mechanisms to increase tumor BCMA expression, and in turn therapeutic efficacy, are ongoing.