Dhakal Binod, Hari Parameswaran, Chhabra Saurabh, Szabo Aniko, Lum Lawrence G, Glass Deborah D, Park Jee Hyun, Donato Michele, Siegel David S, Felizardo Tania C, Fowler Daniel H
Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
J Immunother Cancer. 2025 Jan 28;13(1):e010649. doi: 10.1136/jitc-2024-010649.
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 (T) 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.
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).
From December 2020 to December 2022, 14 patients with RRMM received a median of three RAPA-201 infusions (median dose, 80×10 cells). RAPA-201 drug products (DPs) were: polyclonal; enriched for T 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/M 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.
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.
ClinicalTrials.gov: NCT04176380.
通过mTOR抑制和IFN-α极化进行表观遗传重编程的多克隆自体T细胞（RAPA-201）代表了一种癌症过继性T细胞治疗的新方法。体外抑制mTOR会导致向T中央记忆（Tcm）细胞转变，而体外IFN-α则促进I型细胞因子的产生，已知这些功能中的每一种都能增强癌症的过继性T细胞治疗效果。之前在同种异体移植背景下评估了向II型细胞因子表型极化的雷帕霉素抗性T细胞。
该临床试验（NCT04176380）评估了RAPA-201疗法联合氟达拉滨减量低剂量宿主预处理用于治疗复发、难治性多发性骨髓瘤（RRMM）患者的疗效。
2020年12月至2022年12月，14例RRMM患者接受了中位3次RAPA-201输注（中位剂量，80×10⁶个细胞）。RAPA-201药物产品（DPs）具有以下特点：多克隆；富含T细胞；免疫检查点表达降低，包括PD1、CD73和LAIR1；并优先分泌Th1细胞因子。每个周期给予的化疗药物中位剂量为：环磷酰胺总量1817mg（范围1100 - 2200mg），喷司他丁2.35mg/m²（范围0 - 16mg/m²）。14例患者中有9例（64%）实现疾病缓解，包括8例部分缓解和1例严格完全缓解。中位无进展生存期为6.0个月（范围2.1至>16.8个月）。没有任何归因于RAPA-201的任何级别的毒性反应，包括没有细胞因子释放综合征和没有免疫效应细胞相关神经毒性综合征。14例患者中只有4例（29%）发生了任何归因的严重不良事件（≥3级）。
与我们的假设一致，使用mTOR抑制和IFN-α极化的体外制备方法持续产生了一种新型的RAPA-201 DP，其在细胞因子表型、记忆状态和检查点表达方面具有理想的表型。接受RAPA-201治疗的患者T细胞计数和Th1细胞因子分泌得以保留，但T细胞受体克隆性增加，这与单克隆抗体检查点治疗背景下的抗肿瘤反应相关。RAPA-201疗法克服了以往有效自体多克隆T细胞治疗的障碍，因为它制备可行、给药极其安全，并能使RRMM患者获得缓解。
ClinicalTrials.gov：NCT04176380。
