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Currently approved chimeric antigen receptor (CAR) T cells are designed to recognize and bind to a single cell surface tumor target. While this has been effective treatment approach, malignant cells can develop resistance by concealing the target antigen; hindering treatment efficacy and leading to cancer recurrence and disease progression.1 Dual-targeted CAR T-cell therapy is a therapeutic approach that utilizes two tumor-associated antigens on the surface of cancer cells, with the hopes of improving disease outcomes and reducing the likelihood of relapse or refractory disease by overcoming drug resistance.1
Below, The Lymphoma Hub is happy to provide a brief summary of three key studies on dual-targeted CAR T-cell therapy, as presented at the 2023 Tandem Transplantation and Cellular Therapy Meetings of ASTCT and CIBMTR in Orlando, U.S.
Shah shared a preplanned, interim futility analysis from the ongoing phase II DALY clinical trial (NCT04792489) of zamtocabtagene autoleucel (zamto-cel) for patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). Of the 27 patients currently enrolled in the trial, 22 were evaluable for analysis as per investigational protocol; 82% of evaluable patients had achieved either a complete response (CR) or partial response (PR) by Day 28 of treatment, exceeding the futility threshold. Among the 22 evaluable patients, 68% had high-risk disease with an International Prognostic Index score of ≥3, with 13% having had prior CD19 antibody exposure pre-CAR-cell treatment. In terms of safety, no patients exhibited Grade ≥3 cytokine release syndrome (CRS), while one patient experienced Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS).
The predetermined interim analysis indicates promising efficacy and low toxicity for zamto-cel in patients with pre-treated DLBCL, demonstrating a successful rapid manufacturing process with 100% fresh infusion in eligible patients.
Furqan presented a poster on tandem anti-CD20/anti-CD19 (LV20.19) CAR T-cell therapy in patients with Richter transformation (RT). This included data on patients from two clinical trials (NCT03019055; NCT04186520), with a total of six patients with RT being identified for analysis inclusion. Two patients were treated on the completed study with IL-2 expanded LV20.19 CAR T-cells and four are enrolled in the ongoing IL-7/IL-15 trial. Of the included patients, five had pre-existing chronic lymphocytic leukemia (CLL), while one presented with RT at initial diagnosis. All patients with CLL had received ≥2 lines of CLL-directed therapy, including a Bruton’s tyrosine kinase (BTK) inhibitor. Upon RT diagnosis, all patients received frontline treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy.
The 28-day overall response rate (ORR) was 100% (CR, 60%; PR, 40%), and four patients are maintaining an ongoing response with a median follow-up of 10 months. Median duration of response has not been reached. CRS occurred across all patients but was limited to Grade 1/2. One patient experienced ICANS.
Bispecific LV20.19 CAR T-cell therapy was shown to result in robust early and durable responses in heavily pretreated patients with CLL and RT. LV20.19 CAR T-cell therapy represents a promising new strategy for the treatment of R/R RT.
Dual targeting of CD20 and CD19 with 4-1BB co-stimulatory signaling using LV20.19 CAR T cells was also evaluated in patients with mantle cell lymphoma (MCL). Shah presented the results for this patient population from the ongoing phase I/II study (NCT04186520).
To date, 11 patients have received LV20.19 CAR T cells, with nine patients receiving 8-day manufactured CAR T cells and two patients receiving a 12-day product. Patients had received a median of four previous lines of therapy prior to infusion; nine patients had received a BTK inhibitor, with four of these receiving the non-covalent BTK inhibitor pirtobrutinib.
The Day 28 ORR was 100% (CR, 64%; PR, 36%). Seven patients were minimal residual disease negative as assessed between Days 28 and 60 post CAR T-cell infusion. After a median follow-up of 20 months, no surviving patient had relapsed. One patient died due to gram negative sepsis post 28-day evaluation. All patients experienced Grade 1/2 CRS, with no Grade ≥3 events reported. Two patients experienced ICANS, one Grade 2 and one Grade 3. The 1-year progression-free survival and overall survival rates were both 91%.
Bispecific LV20.19 CAR T cells expanded with IL-7/IL-15 appear to be a safe and efficacious therapeutic strategy for patients with for R/R MCL. Dual targeting of CD19 and CD20 with CAR T cells may improve outcomes in pts with R/R MCL.
The above data indicates that dual targeting CAR T-cell therapy may represent an effective treatment strategy for patients with B-cell malignancies. The promising efficacy and acceptable safety profiles are encouraging for future research.
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