Background Polyclonal RAPA-201 is enriched for central-memory, polarized to Th1/Tc1, and rendered immune checkpoint-deficient and homeostatic cytokine-responsive.¹ RAPA-201 safely mediates disease remissions in multiple myeloma when administered after lymphodepleting conditioning.² RAPA-201 is also resistant to chemotherapy, including carboplatin (CBCCA), paclitaxel (PTX), and topotecan (Park JH et al, separate abstract submitted to SITC 2023). Given this background, we hypothesized that RAPA-201, when administered with immune-sparing CBCCA/PTX conditioning, would safely mediate disease regression in solid tumor patients in the post-PD-(L)1 setting.

Methods Accrual involved patients with metastatic solid tumors relapsed or refractory to standard treatments, including an anti-PD-(L)1 containing regimen just prior to study entry. Autologous RAPA-201 were manufactured using one-week culture in temsirolimus- and IFN-α-containing media (cryopreserved, 80–400 x 10⁶ cells). Chemotherapy for bridging and RAPA-201 conditioning consisted of CBCCA (target AUC, 2 mg/mL/min) and PTX (80 mg/m²) (each agent IV on days 1, 8, and 15; 28-day cycle). RAPA-201 were infused IV on cycle day 3 (up to four RAPA-201 cycles). Objectives were to confirm RAPA-201 safety and determine response rate (iRECIST Criteria) using Simon’s two-stage design (≥ 2/10 responses [≥PR] required for second-stage accrual [overall goal, ≥ 6/22 responses]).

Results Ten enrolled patients are evaluable (table 1; data as of 6/24/2023). RAPA-201 was manufactured in 10/10 patients, who generally had widely metastatic and bulky disease (target lesions, SLD: median, 10 cm). RAPA-201 cycles (n=29) were administered exclusively outpatient (median RAPA-201 dose, 100 x 10⁶ cells). RAPA-201 was safely administered (no CRS, ICANS, or autoimmunity); CBCCA/PTX conditioning was not significantly immune-depleting (median reduction in ALC, 12.5%). RAPA-201 yielded partial responses in 3/5 melanoma patients (PFS as long as 15.1 months) and 2/5 lung cancer patients (both small cell-type).

Conclusions A new adoptive cell therapy paradigm now emerges whereby metabolically fit T cells with a true polyclonal TCR repertoire target potential tumor antigens in vivo without lymphodepletion. The exquisite safety of the RAPA-201 platform likely reflects natural T cell signaling, lack of homeostatic cytokine spikes, and host immune cell sparing. And, the remarkable RAPA-201 response rate (overall, 50%) for end-stage malignancy likely emanates from an ability of functionally-optimized T cells to target tumors in the context of disease-specific, immune-sparing conditioning. Ongoing efforts seek to characterize RAPA-201 mechanism of action, breakout clinical trial efforts in responsive tumor types (melanoma, SCLC), and continue evaluation of RAPA-201 in potentially sensitive tumor types (NSCLC, head and neck, gastric, bladder, triple-negative breast, and renal cell).

Acknowledgements The authors would like to thank all study subjects for their participation and acknowledge the numerous individuals at HUMC and RAPA who contributed to the implementation of this study. This study was funded by RAPA.

Trial Registration NCT05144698

References

1. Felizardo T, Mosquera Limas S, Zhu N, Bushera H, Glass D, Hari, P, Dhakal B, Fowler DH. Temsirolimus-resistant, checkpoint-deficient, homeostatic cytokine-responsive autologous Th1/Tc1 cells for therapy of relapsed, refractory multiple myeloma. Cytotherapy 2021;23(5):Supplement S86. DOI: https://doi.org/10.1016/S1465324921004011.

2. Dhakal B, Felizardo T, Lum LG, D’Souza A, Chhabra S, Keaton T, Mohan M, Park JH, Fowler DH, Hari P. Metabolically Reprogrammed Polyclonal Autologous Rapa-201 Cell Therapy Yields a Promising Safety and Efficacy Profile in Relapsed and Refractory Multiple Myeloma (RRMM). Blood 2021;138(Supplement 1):2838. DOI: 10.1182/blood-2021–147478.

Ethics Approval The study was approved by the WCG-IRB on 06/10/2021 (Study Number, 1310232).

Consent All participants provided written informed consent before enrollment.