Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed,...

Area of Science:

• Immunology
• Oncology
• Cellular Therapy

Background:

• Polyclonal autologous T cells epigenetically reprogrammed via mTOR inhibition and IFN-α polarization (RAPA-201) offer a novel adoptive T cell therapy for cancer.
• Ex vivo mTOR inhibition promotes T central memory (TCM) cells, while IFN-α polarization enhances type I cytokines, both known to improve adoptive T cell therapy efficacy.
• Previous studies evaluated rapamycin-resistant T cells with a type II cytokine phenotype in allogeneic transplantation.

Purpose of the Study:

• To evaluate the safety and efficacy of RAPA-201 therapy in patients with relapsed, refractory multiple myeloma (RRMM).
• To assess RAPA-201 in combination with fludarabine-sparing low-dose host conditioning.

Main Methods:

• A clinical trial (NCT04176380) involved 14 patients with RRMM receiving RAPA-201 therapy.
• RAPA-201 drug products were polyclonal, enriched for TCM cells, reduced for immune checkpoints (PD1, CD73, LAIR1), and secreted Th1 cytokines.
• Patients received a median of three RAPA-201 infusions alongside chemotherapy (cyclophosphamide and pentostatin).

Main Results:

• Nine out of 14 patients (64%) achieved disease remission, including eight partial responses and one stringent complete response.
• The median progression-free survival was 6.0 months.
• No toxicities were attributed to RAPA-201, with no cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome observed. Only 29% of patients experienced serious adverse events.

Conclusions:

• Ex vivo manufacturing of RAPA-201 using mTOR inhibition and IFN-α polarization yielded a product with a desirable phenotype.
• RAPA-201 recipients maintained T cell counts and Th1 cytokine secretion, with increased T cell receptor clonality potentially enhancing antitumor responses.
• RAPA-201 therapy is feasible, safe, and effective in inducing remission in RRMM patients, overcoming previous limitations of autologous polyclonal T-cell therapy.