{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T00:51:57Z","timestamp":1759539117241,"version":"build-2065373602"},"reference-count":30,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T00:00:00Z","timestamp":1738022400000},"content-version":"unspecified","delay-in-days":27,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,1,15]]},"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Polyclonal autologous T cells that are epigenetically reprogrammed through mTOR inhibition and IFN-\u03b1 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 (T<jats:sub>CM<\/jats:sub>) whereas ex vivo IFN-\u03b1 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The clinical trial (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04176380\">NCT04176380<\/jats:ext-link>) evaluated RAPA-201 therapy in combination with fludarabine-sparing low-dose host conditioning for the treatment of patients with relapsed, refractory multiple myeloma (RRMM).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>From December 2020 to December 2022, 14 patients with RRMM received a median of three RAPA-201 infusions (median dose, 80\u00d710<jats:sup>6<\/jats:sup> cells). RAPA-201 drug products (DPs) were: polyclonal; enriched for T<jats:sub>CM<\/jats:sub> 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\u2009mg total for cyclophosphamide (range, 1,100\u20132,200) and 2.35 mg\/M<jats:sup>2<\/jats:sup> for pentostatin (range, 0\u201316). 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&gt;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 (\u2265 grade 3) of any attribution.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Consistent with our hypothesis, ex vivo manufacturing using mTOR inhibition and IFN-\u03b1 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>ClinicalTrials.gov: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04176380\">NCT04176380<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-010649","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T12:01:24Z","timestamp":1738065684000},"page":"e010649","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Rapamycin-resistant polyclonal Th1\/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct04176380","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04176380","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04176380","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04176380","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05144698","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4377-9742","authenticated-orcid":false,"given":"Binod","family":"Dhakal","sequence":"first","affiliation":[{"name":"Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parameswaran","family":"Hari","sequence":"additional","affiliation":[{"name":"Medical College of Wisconsin, Milwaukee, Wisconsin, USA"},{"name":"Obsidian Therapeutics, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saurabh","family":"Chhabra","sequence":"additional","affiliation":[{"name":"Medical College of Wisconsin, Milwaukee, Wisconsin, USA"},{"name":"Mayo Clinic, Phoenix, Arizona, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aniko","family":"Szabo","sequence":"additional","affiliation":[{"name":"Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7561-6035","authenticated-orcid":false,"given":"Lawrence G","family":"Lum","sequence":"additional","affiliation":[{"name":"University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah D","family":"Glass","sequence":"additional","affiliation":[{"name":"Rapa Therapeutics, Rockville, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jee 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