Contributions
Abstract: EP731
Type: E-Poster Presentation
Session title: Gene therapy, cellular immunotherapy and vaccination - Clinical
Background
Immunotherapy with CD19 targeting CAR-T has become a standard treatment for patients (pts) with relapsed diffuse large cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) and clinical trials have shown high efficacy in other B-NHLs. However, long-term remissions for the approved indications are ~40%, and toxicities including cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain a challenge. CD20 is a proven target for treatment of B-NHLs/ CLL with demonstrated high clinical efficacy of unmodified, radiolabeled, and bispecific antibodies. CD20-targeted CAR-T represents a promising adoptive immunotherapy option that could be utilized to treat relapsed/refractory B-NHLs and CLL.
Aims
We present interim results of our ongoing phase I/II clinical trial investigating safety and efficacy CD20 CAR-T for high-risk B-NHLs and CLL (NCT03277729).
Methods
MB-106 is a fully human 3rd-generation CD20-targeted CAR-T with both 4-1BB and CD28 costimulatory domains. Lymphodepletion (LD) consists of cyclophosphamide (Cy) ± fludarabine (Flu). CAR-T cells are administered at one of 4 dose levels (DL): DL1: 3.3x105, DL2: 1x106, DL3: 3.3x106, DL4: 1x107 CAR T cells/kg. CAR-T is infused in the outpatient setting except for the first pt of each dose cohort (overnight observation). Pts with relapsed CD20+ B-cell malignancies are eligible, including but not limited to DLBCL, follicular lymphoma (FL), MCL and CLL. Prior treatment with CD19 CAR-T is permitted. Treatment response is assessed on day 28. CRS and ICANS are graded per ASTCT consensus grading.
Results
The study underwent a major cell manufacturing modification after treating 7 pts with no objective responses as previously reported (Shadman, ASH 2020). This abstract includes pts who were treated under the modified process. Since December 2019, 12 pts (9 FL, 2 MCL, 1 CLL) were treated after LD with Cy-Flu. All DLs have been reached: DL0 (1 FL), DL1 (2 FL), DL2 (2 FL and 2 MCL), DL3 (3 FL, 1 CLL) and DL4 (1 FL), with no dose-liming toxicities. CRS occurred in 3 pts (25%): 2 pts with grade (Gr) 1 and 1 pt with Gr 2. Only 1 pt required tocilizumab and dexamethasone. No ICANS of any grade was observed. One pt developed Gr 3 neuropathic pain which, in the absence of other explanation, was attributed to the CAR-T. No pts had tumor lysis syndrome or Gr 3-4 infection. Clinical responses were observed at all dose levels. Overall response rate (ORR) was 92% (11/12) with a complete response (CR) rate of 58% (7/12). In FL pts (n=9), ORR and CR were 89% (8/9) and 67% (6/9), respectively. The CLL pt had a PET-negative CR and undetectable measurable residual disease in peripheral blood and bone marrow by flow cytometry (10-4) (uMRD4) on day 28. Among pts who received DL3 (n=4) and DL4 (n=1), CR rate was 100% (5/5). All 7 pts who achieved a CR remain in remission at a median follow-up of 4 months (range 0 – 13 months). CAR-T expansion was robust, with median peak blood levels of CAR+ T cells of 122 CAR+ cells/µl (range 0.27-2024), corresponding to 19% (range 0.15 - 65%) of all CD3+ cells.
Conclusion
The absence of significant toxicity at all dose levels, including no grade 3-4 CRS and no ICANS of any grade, suggests a highly favorable safety profile of MB-106 when compared to commercially available CAR-T cells targeting CD19. Treatment with MB-106 has also resulted in high ORR and CR rates with ongoing remissions in all patients who achieved a CR. Enrollment is currently ongoing and the data will be updated at the time of presentation.
Keyword(s):
Abstract: EP731
Type: E-Poster Presentation
Session title: Gene therapy, cellular immunotherapy and vaccination - Clinical
Background
Immunotherapy with CD19 targeting CAR-T has become a standard treatment for patients (pts) with relapsed diffuse large cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) and clinical trials have shown high efficacy in other B-NHLs. However, long-term remissions for the approved indications are ~40%, and toxicities including cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain a challenge. CD20 is a proven target for treatment of B-NHLs/ CLL with demonstrated high clinical efficacy of unmodified, radiolabeled, and bispecific antibodies. CD20-targeted CAR-T represents a promising adoptive immunotherapy option that could be utilized to treat relapsed/refractory B-NHLs and CLL.
Aims
We present interim results of our ongoing phase I/II clinical trial investigating safety and efficacy CD20 CAR-T for high-risk B-NHLs and CLL (NCT03277729).
Methods
MB-106 is a fully human 3rd-generation CD20-targeted CAR-T with both 4-1BB and CD28 costimulatory domains. Lymphodepletion (LD) consists of cyclophosphamide (Cy) ± fludarabine (Flu). CAR-T cells are administered at one of 4 dose levels (DL): DL1: 3.3x105, DL2: 1x106, DL3: 3.3x106, DL4: 1x107 CAR T cells/kg. CAR-T is infused in the outpatient setting except for the first pt of each dose cohort (overnight observation). Pts with relapsed CD20+ B-cell malignancies are eligible, including but not limited to DLBCL, follicular lymphoma (FL), MCL and CLL. Prior treatment with CD19 CAR-T is permitted. Treatment response is assessed on day 28. CRS and ICANS are graded per ASTCT consensus grading.
Results
The study underwent a major cell manufacturing modification after treating 7 pts with no objective responses as previously reported (Shadman, ASH 2020). This abstract includes pts who were treated under the modified process. Since December 2019, 12 pts (9 FL, 2 MCL, 1 CLL) were treated after LD with Cy-Flu. All DLs have been reached: DL0 (1 FL), DL1 (2 FL), DL2 (2 FL and 2 MCL), DL3 (3 FL, 1 CLL) and DL4 (1 FL), with no dose-liming toxicities. CRS occurred in 3 pts (25%): 2 pts with grade (Gr) 1 and 1 pt with Gr 2. Only 1 pt required tocilizumab and dexamethasone. No ICANS of any grade was observed. One pt developed Gr 3 neuropathic pain which, in the absence of other explanation, was attributed to the CAR-T. No pts had tumor lysis syndrome or Gr 3-4 infection. Clinical responses were observed at all dose levels. Overall response rate (ORR) was 92% (11/12) with a complete response (CR) rate of 58% (7/12). In FL pts (n=9), ORR and CR were 89% (8/9) and 67% (6/9), respectively. The CLL pt had a PET-negative CR and undetectable measurable residual disease in peripheral blood and bone marrow by flow cytometry (10-4) (uMRD4) on day 28. Among pts who received DL3 (n=4) and DL4 (n=1), CR rate was 100% (5/5). All 7 pts who achieved a CR remain in remission at a median follow-up of 4 months (range 0 – 13 months). CAR-T expansion was robust, with median peak blood levels of CAR+ T cells of 122 CAR+ cells/µl (range 0.27-2024), corresponding to 19% (range 0.15 - 65%) of all CD3+ cells.
Conclusion
The absence of significant toxicity at all dose levels, including no grade 3-4 CRS and no ICANS of any grade, suggests a highly favorable safety profile of MB-106 when compared to commercially available CAR-T cells targeting CD19. Treatment with MB-106 has also resulted in high ORR and CR rates with ongoing remissions in all patients who achieved a CR. Enrollment is currently ongoing and the data will be updated at the time of presentation.
Keyword(s):