Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma
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 viv...
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e010649.full |
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| author | Lawrence G Lum Parameswaran Hari Aniko Szabo Michele Donato Jee Hyun Park Daniel H Fowler Binod Dhakal Saurabh Chhabra Deborah D Glass David S Siegel Tania C Felizardo |
| author_facet | Lawrence G Lum Parameswaran Hari Aniko Szabo Michele Donato Jee Hyun Park Daniel H Fowler Binod Dhakal Saurabh Chhabra Deborah D Glass David S Siegel Tania C Felizardo |
| author_sort | Lawrence G Lum |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6c5569fecd804e0fbd2c9d57cb3a761a |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-6c5569fecd804e0fbd2c9d57cb3a761a2025-01-29T05:45:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-010649Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myelomaLawrence G Lum0Parameswaran Hari1Aniko Szabo2Michele Donato3Jee Hyun Park4Daniel H Fowler5Binod Dhakal6Saurabh Chhabra7Deborah D Glass8David S Siegel9Tania C Felizardo10University of Virginia, Charlottesville, Virginia, USAMedical College of Wisconsin, Milwaukee, Wisconsin, USAMedical College of Wisconsin, Milwaukee, Wisconsin, USAHackensack University Medical Center, Hackensack, New Jersey, USARapa Therapeutics, Rockville, Maryland, USARapa Therapeutics, Rockville, Maryland, USAMedical College of Wisconsin, Milwaukee, Wisconsin, USAMedical College of Wisconsin, Milwaukee, Wisconsin, USARapa Therapeutics, Rockville, Maryland, USAHackensack University Medical Center, Hackensack, New Jersey, USARapa Therapeutics, Rockville, Maryland, USABackground 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.https://jitc.bmj.com/content/13/1/e010649.full |
| spellingShingle | Lawrence G Lum Parameswaran Hari Aniko Szabo Michele Donato Jee Hyun Park Daniel H Fowler Binod Dhakal Saurabh Chhabra Deborah D Glass David S Siegel Tania C Felizardo Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma Journal for ImmunoTherapy of Cancer |
| title | Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma |
| title_full | Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma |
| title_fullStr | Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma |
| title_full_unstemmed | Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma |
| title_short | Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma |
| title_sort | rapamycin resistant polyclonal th1 tc1 cell therapy rapa 201 safely induces disease remissions in relapsed refractory multiple myeloma |
| url | https://jitc.bmj.com/content/13/1/e010649.full |
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