Highlights from Dec. 2, 2018
Phase 1/2 TRANSCEND CLL 004 clinical trial data suggest promising safety and efficacy of anti-CD19 CAR T therapy lisocabtagene maraleucel in patients with chronic lymphocytic leukemia
Tanya Siddiqi, MD (City of Hope National Medicine Center, Duarte, Calif., USA), presented data from the phase 1/2 TRANSCEND CLL 004 trial evaluating safety and efficacy of the anti-CD19 CAR T therapy lisocabtagene maraleucel (liso-cel) for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In all, 16 patients (median age – 64.5 years [51 – 76], 16 = prior ibrutinib, eight = prior ibrutinib + venetoclax) received liso-cel at one of two doses: DL1 (5 x 107 cells, n = six) and DL2 (1 x 108 cells, n = ten) following three-day lymphodepletion via fludaribine (30mg/m2) and cyclophosphamide (300mg/m2). One dose-limiting toxicity of grade four hypertension was observed in the DL2 cohort. 7/16 (43.8 percent) patients experienced grade 3/4 adverse events. 75 percent (12/16) of patients experienced cytokine release syndrome (CRS, DL1 = 6/6, DL2 = 6/10, grade 1/2 = 11, grade 3 = one). Six patients experienced neurotoxicities, three of which were grade 3 (DL1 = two, DL2 = one). At 30 days post-infusion, the overall response rate (ORR) in all patients was 75 percent (five complete responses [CR], seven partial responses [PR]), with CR observed across dosage cohorts (DL1 = three, DL2 = two). Three-month ORR was in all patients was 80 percent (five CR, three PR). 11/15 evaluable patients had minimal residual disease (MRD) –negative status, all of which continue to have undetectable disease at latest follow-up. Median time to peak expansion was 16 days (4 – 30). Preliminary biomarker analyses reveal elevated levels of IL-16 and TNF in prior to the onset of neurological events in 3/4 patients. In summary, these promising data suggest efficacy and tolerability of lisocabtagene maraleucel for the treatment of heavily pretreated CLL patients.
CAR T therapies targeting immunoglobulin kappa or lambda may provide anti-tumor activity while reducing off-tumor cytotoxicity
Raghuveer Ranganathan, MD (University of North Carolina at Chapel Hill, Chapel Hill, N.C., USA), presented pre-clinical research investigating whether CAR T therapies targeting B cell surface immunoglobulin kappa (Ig-k) or lambda (Ig-l) light chains presented by malignant B cell lymphomas could retain anti-tumor efficacy while sparing elimination of non-cancerous B cells. Data suggest that 60-70 percent of mature B cell lymphomas express Ig-k, while 30-40 percent express Ig-l. In vitro experiments reveal that CAR T cells that target Ig-k or Ig-l selectively eradicate respective Ig-k/ Ig-l expressing tumor-cell lines (Daudi = CD19-positive, Ig-k positive, Ig-l negative; Maver-1= CD19-positive, Ig-k negative, Ig-l positive) to a similar degree as anti-CD19 CAR T cells. Further studies indicate that anti-Ig-l CAR T cells have anti-tumor activity against human Ig-l-expressing CLL cells. Anti-Ig-l CAR T cells increased survival of mice bearing CD19-positive, Ig-l positive, lg-k-negative lymphoma tumors compared to mice treated with anti-Ig-k CAR T cells (n= five each, p less that 0.0001). Additionally, no statistical difference was observed in survival of mice treated with anti-CD19 or anti-Ig-l CAR T cells. Importantly, while in vitro experiments reveal that anti-CD19 CAR T cells eliminate non-cancerous human B cells, anti-Ig-k CAR T cells displayed no observable cytotoxicity. Together, these data suggest that targeting Ig-k or Ig-l on clonally restricted B cell lymphomas via CAR T therapy may be a potential mechanism to limit on-target off-tumor toxicity and associated B cell aplasia often observed in treated patients.
Pre-treatment of cord blood derived natural killer cells with the CD30/CD16A bispecific antibody AFM13 increases pre-clinical anti-tumor efficacy against CD30+ malignancies
Lucila Kerbauy, MD (MD Anderson Cancer Center, Houston, Tx., USA), discussed pre-clinical research evaluating anti-tumor activity of allogeneic Natural Killer (NK) cells derived from cord blood (CB) pre-treated with the CD30/CD16A bispecific antibody AFM13 for the treatment of patients with CD30+ hematologic malignancies. Previous studies indicate that CB-derived NK cell therapies are safe in humans and may serve as potential “off the shelf” treatments for various forms of cancer, and that NK cell effector function is impaired in patients with Hodgkin lymphoma. To further this potential therapeutic modality, researchers expanded CB-derived CD56+ NK cells ex vivo in the presence of IL-18, IL-12, and IL-15, and subsequently loaded cells with serial dilutions of AFM13 (0.1 – 100 mg/ml) that associates with NK cell CD16A. Results suggest that 100ug/mL AFM13-NK cells had increased cytotoxicity against CD30+ Karpas-299 lymphoma cells compared to unloaded NK cells, but were unable to kill CD30-negative Daudi lymphoma cells. AFM13-NK cells also displayed increased secretion of IFNgamma, TNFalpha, and CD107a secretion compared to unloaded NK cells (each p less than 0.05). Washing of AFM13-NK cells had no effect on effector function, suggesting that AFM13/CD16A interactions are durable. Survival of mice bearing CD30+ Karpas-299 lymphoma tumors was increased with AFM13-NK cells compared to unloaded NK cell therapy, results of which correlated with a decrease in tumor burden. Flow cytometry analyses reveal that AFM13-NK cells localized and interacted with disease sites. Together, these pre-clinical data suggest that CB-derived NK cells treated with AFM13 may serve as a potential “off the shelf” treatment option for patients with CD30+ malignancies. An early clinical trial of this therapy in humans is currently planned.
Phase 1 clinical trial data suggest the CD20/CD3 bispecific antibody mosunetuzumab provides safe and durable responses for patients with relapsed/refractory non-Hodgkin lymphoma
Lihua Budde (City of Hope National Medicine Center, Duarte, Calif., USA), presented phase 1/1b clinical trial results (NCT02500407) evaluating the safety and efficacy of mosunetuzumab – an anti-CD20/CD3 bispecific antibody - for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma. In all, 131 patients (median age = 63 [19-85]) were assigned to receive mosunetuzumab Q3W either as a fixed dose (Group A, 0.5mg - 2.8mg, n = 33) or through step-up dosing on cycle 1 (Group B, 0.4/1/2.8mg on D1, 8, and 15 of cycle one, 1/2/20mg Q3W starting cycle two, n = 98). Grade three treatment-related adverse events were observed in 34 patients (26 percent), most commonly neutropenia (n = 15), hypophosphatemia (n = seven), and anemia (n = four). Three deaths occurred, one each due to macrophage activation syndrome, candida sepsis, and disease-related large intestine perforation. 23 percent of patients (n = 30) experienced grade 1/2 CRS (Lee criteria), and no grade three events were observed. 49 percent of patients (n = 64) experienced neurotoxicities with three grade three events. Notably, the MTD has not yet been reached with most AE being mild, transient, and reversible occurring predominantly in cycle one. ORR in patients with relapsed/refractory DLBCL or transformed follicular lymphoma (FL) was 34 percent (16/47) with 19 percent of patients achieving CR (n = nine). At median-follow up of 298 days (46 – 816), the median duration of response (DOR) for patients in CR had not yet been reached. In patients with relapsed/refractory FL (n = 26), ORR was 69 percent (n = 18) with ten patients achieving CR (38.5 percent). Similarly, median DOR in patients with FL who achieved CR has not yet been reached at median follow up of 330 days (54 – 788). These early data indicate that mosunetuzumab provides acceptable safety as well as durable responses for patients with relapsed/refractory non-Hodgkin lymphoma and is in being investigated in combination with chemotherapy, atezolizumab, or polatuzumab vedotin.
Early Phase 1 clinical trial results suggest promising safety and efficacy of bb21217 – a next-generation anti-BCMA CAR T therapy – for the treatment of patients with multiple myeloma
Nina Shah, MD (University of California, San Francisco, San Francisco, Calif., USA), presented preliminary results from the phase 1 CRB-402 clinical trial (NCT03274219) evaluating safety and efficacy of the anti-BCMA CAR T therapy bb21217 in patients with relapsed/refractory multiple myeloma. Bb21217 is a next-generation CAR T therapy that contains an scFv, 4-1BB costimulatory motif and CD3-zeta T cell activation domain and is treated with the phosphoinositide 3 kinase inhibitor bb007 during ex vivo culture to help enrich for memory T cells and enhance the durability of anti-tumor activity. In all, 12 patients (median age = 63 [44 – 69], with history of greater than three prior therapies, and prescreened for greater than 50 percent BCMA expression) underwent lymphodepletion (fludarabine [30 mg/m2] and cyclophosphamide [300 mg/m2] daily for three days) before receiving 150 x 106 bb21217 cells via a single infusion. Eight patients developed CRS (67 percent, grade one = four, grade two = three, grade three = one). Grade 1/2 neurotoxicities were observed in two patients. One patient with a high tumor burden and rapidly accelerating disease experienced dose-limiting CRS and grade four encephalopathy that was resolved via tocilizumab, corticosteroids, and cyclophosphamide. Of note, grade 3/4 neutropenia was observed in eight percent and 75 percent of patients, respectively, 11/12 of which recovered at least by day 65. ORR was 83.3 percent (95 percent CI: 51.6 – 97.9), with three CR and six greater than VGPR. In one case, a patient achieved CR ten months post-infusion, suggesting that responses can deepen over time. All but one responder remain in ongoing response, with one patient experiencing greater than one year of remission. All four evaluable patients for MRD status are MRD-negative. Importantly, memory CAR T cell expansion was observed in patient blood post-infusion, and CAR T cells remained detectable up to nine months post-infusion. Together, these preliminary data suggest that bb21217 is well tolerated and may be effective in treating patients with relapsed/refractory multiple myeloma. This study is ongoing.