Safety, Efficacy and Total Cost of Therapy of Decentralized, Point-of-Care Manufactured Anti-CD19 CAR-T Cells for Relapsed or Refractory B Cell Leukemia and Lymphoma: Results from the First Phase 1 Indian Trial (VELCART)

Background

Anti-CD19 CAR-T cells are an effective therapeutic modality against relapsed/ refractory CD19+ve B-cell leukemia and lymphomas (r/r B-cell ALL/Lym). Decentralized or point-of-care manufacturing using fresh products and a short vein-to-vein time can potentially improve access and efficacy of CAR-T cell therapy while reducing logistic challenges and costs. These are especially relevant in low/ middle-income countries (LMIC) like India.

Methods

Patients aged 2 to 60 years with r/r B-cell ALL/ Lym who failed ≥ 2 lines of therapy with ECOG PS ≥2 and measurable disease were enrolled. Autologous T cells were transduced with an anti-CD19 second-generation lentiviral vector (LTG1563, Lentigen, Miltenyi Biotec). GMP-compliant CAR-T cell manufacture was done using the CliniMACS prodigy system in a 9-day culture protocol. Phase 1 study was designed with a dose escalation strategy of 3+3 design with increasing doses at each level. Lymphodepletion was done with Cyclophosphamide 40-60 mg/ kg on day -6 and Fludarabine 30 mg/ m² daily on days -5 to -2. The response was assessed by bone marrow (BM) minimal residual disease by multi-parametric flow cytometry (MFC) for B cell leukemia and PET-CT for B-cell lymphoma per NCCN and IWG criteria. The CRS and ICANS were graded and treated as per ASTCT guidelines. Hematotoxicity was graded as per EHA/ EBMT recommendations, and other toxicities were graded as per CTCAE v5.

Results

A total of 10 patients with r/ r B-ALL (n=6) and Lym (n=4) were enrolled, with a median age of 45 years (range 6-59). Patients had a median of 3 lines of therapy (range 2-6). In the B-ALL cohort, 5/6 had refractory disease with a BM blast percentage detectable only on MFC (range 0.06-2.27%), and 1/6 had bulk disease with a BM blast percentage of 28%. In the lymphoma cohort, 2/ 4 had refractory disease, and the other two had relapsed and progressive disease.

The vein-to-vein time was nine days, and the manufacture of CAR-T cell product was successful in all patients. The median transduction rate was 38% (range 16-55), and the median culture expansion was 15-fold (range 1-33). Immunophenotypic characterization demonstrated an increase in central memory cells followed by effector cells. All the patients were infused with fresh CAR-T cells. The cell doses were 0.5 X 10⁶ / Kg (n=3), 1 X 10⁶ / Kg (n=3), and 2 X 10⁶ / Kg (n=4). CAR-T cell persistence by flow cytometry demonstrated a peak in peripheral blood mononuclear cells between days 14-21. The median hospitalization period post CAR-T cell infusion was 14 days (range 14-20).

Adverse events of special interest reported were CRS ≥ grade 2 in 2/10 patients (20%; one each grade 2 and 3). None of the patients developed ICANS. Early hematological toxicity (ICAHT), ≥ grade 2-3 neutropenia, was seen in 3 patients (30%). Among ten patients evaluable for response, 6/ 6 B-ALL patients (100%) achieved MRD negative by day 90. In contrast, among the DLBCL, 2/ 4 (50%) achieved complete remission (CR), one patient had a partial response, and another patient in the first cohort with the lowest cell dose did not respond and died very early due to progressive disease. At a median follow-up of 6 months, 9/ 10 patients remain without disease progression. In the B-ALL cohort, 2/ 6 patients underwent HSCT on day +76 and day +60. Both patients remained MRD negative post-HSCT, but one of them died on day +152 from GVHD.

We have previously demonstrated the production cost per product based on a micro-costing analysis of USD 35,107, excluding the cost of the lentiviral vector (Palani et al., BMT 2022). This study's post-manufacturing cost analysis for healthcare resource utilization/ clinical management per patient for leukemia and lymphoma, including ICU admission and management of adverse events and follow-up, demonstrated that the median cost was USD 12,724.

Conclusion

Data from 10 patients enrolled in this phase 1 VELCART trial demonstrates that decentralized, point-of-care manufacturing of CAR-T cells with nine days vein-to-vein time is feasible using the CliniMACS prodigy system. The safety profile of this CAR-T cell product is comparable to other CAR-T cell therapies, with high CR rates across different doses in heavily pre-treated patients. Our data highlights the safety, efficacy, low cost, and potential to improve accessibility of CAR-T cell therapy in LMIC using a fully automated point-of-care manufacturing platform.