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Published on: February 17, 2022
Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed,
Binod Dhakal1, Parameswaran Hari2,3, Saurabh Chhabra2,4
1Medical College of Wisconsin, Milwaukee, Wisconsin, USA bdhakal@mcw.edu.
Background:
Polyclonal autologous T cells that are epigenetically reprogrammed through mTOR inhibition and IFN-α polarization (RAPA-201) represent a novel approach to the adoptive T cell therapy of cancer. Ex vivo inhibition of mTOR results causes a shift towards T central memory (TCM) whereas ex vivo IFN-α promotes type I cytokines, with each of these functions known to enhance the adoptive T cell therapy of cancer. Rapamycin-resistant T cells polarized for a type II cytokine phenotype were previously evaluated in the allogeneic transplantation context.
Methods:
The clinical trial (NCT04176380) evaluated RAPA-201 therapy in combination with fludarabine-sparing low-dose host conditioning for the treatment of patients with relapsed, refractory multiple myeloma (RRMM).
Results:
From December 2020 to December 2022, 14 patients with RRMM received a median of three RAPA-201 infusions (median dose, 80×106 cells). RAPA-201 drug products (DPs) were: polyclonal; enriched for TCM cells; reduced for immune checkpoint expression, including PD1, CD73, and LAIR1; and preferentially secreted Th1 cytokines. The median chemotherapy dose administered per cycle was 1,817 mg total for cyclophosphamide (range, 1,100-2,200) and 2.35 mg/M2 for pentostatin (range, 0-16). Nine of 14 patients (64%) achieved disease remission, with eight partial responses and one stringent complete response. Median progression-free survival was 6.0 months (range, 2.1 to>16.8 months). There were no toxicities of any grade attributable to RAPA-201, including no cytokine release syndrome and no immune effector cell-associated neurotoxicity syndrome. Only 4 of 14 patients (29%) had a serious adverse event (≥ grade 3) of any attribution.
Conclusions:
Consistent with our hypothesis, ex vivo manufacturing using mTOR inhibition and IFN-α polarization consistently yielded a novel RAPA-201 DP that possessed a desirable phenotype relative to cytokine phenotype, memory status, and checkpoint expression. RAPA-201 recipients had preservation of T cell counts and Th1 cytokine secretion yet had increased T cell receptor clonality that associates with antitumor responses in the setting of monoclonal antibody checkpoint therapy. RAPA-201 therapy overcomes previous barriers to effective autologous polyclonal T-cell therapy, as it is feasible to manufacture, exquisitely safe to administer, and mediates remission in patients with RRMM.
Trial Registration Number:
ClinicalTrials.gov: NCT04176380.
Insights
Novel RAPA-201 cell therapy, using mTOR inhibition and IFN-α polarization, shows promise for relapsed multiple myeloma. This safe and feasible treatment achieved remission in 64% of patients, offering a new option for advanced cancer.
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.
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