Dual-targeted CAR T-cell therapy: Key updates from TCT 2023

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.

Interim analysis of a phase II study of administered fresh bispecific anti-CD20/anti-CD19 CAR T-cell therapy - zamtocabtagene autoleucel (zamto-cel) for relapsed/refractory (R/R) DLBCL (DALY II USA NCT04792489)²

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).

Author’s conclusions

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.

Bispecific anti-CD20/anti-CD19 (LV20.19) CAR T-cells for Richter’s transformation³

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.

Author’s conclusions

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.

Results from a phase I/II study of tandem, bispecific anti-CD20/anti-CD19 (LV20.19) CAR T-cells for mantle cell lymphoma⁴

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%.

Author’s conclusions

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.

Conclusion

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.