Autologous Rapamycin-Resistant T Cell Therapy of Multiple Myeloma

Adoptive T cell therapy using type I polarized cells represents an approach to prevent multiple myeloma (MM) progression after autologous HSCT. We previously found that type I polarized, rapamycin-resistant T (T1-Rapa) cells mediated increased xenogeneic GVHD (Amarnath et al; Autophagy, 2010); however, we reasoned that T1-Rapa cells might be safe in an autologous setting. In a pilot clinical trial (NCT01239368), we conducted a dose escalation study of T1-Rapa cells. Prior to autologous HSCT, patients with high-risk MM based on cytogenetics or ISS score underwent steady-state apheresis, lymphocyte enrichment, and T cell culture using anti-CD3/CD28 beads, IL-2, IFN-a, and rapamycin. After recovery from single or tandem autologous HSCT (≥42 days post-HSCT), cryopreserved T1-Rapa cells were thawed and infused in a dose escalation manner (Table 1); no post-HSCT maintenance therapy was administered. In a final cohort, T1-Rapa cells were infused alone (cycle 1) and ≥ one month later (cycle 2) after a 7-day regimen of pentostatin (days 1, 5) and dose-adjusted, low-dose oral cyclophosphamide (days 1-7; PC regimen). Toxicities were monitored by NCI-CTCAE criteria whereas the IMWG criteria were used for myeloma grading. Ex vivo manufacture of T1-Rapa cells was feasible in each accrued patient. 20 patients received autologous HSCT followed by T1-Rapa cells. Even at the highest dose evaluated (15 x 106 cells/kg), there were no adverse events attributable to T1-Rapa cells by NCI-CTCAE criteria. The PC regimen achieved lymphocyte depletion (ALC reduction, 88% [avg]) while preserving neutrophils (ANC >1000 cells/μl); there were no adverse events attributable to T1-Rapa infusion (5 x 106 cells/kg) when administered after the PC regimen. Five of 20 high-risk MM patients remain in stringent complete remission at a median of 847 days post-HSCT (range, 733 to 1186 days). Autologous T1-Rapa cells were safe at 15 x 106 cells/kg and safe at 5 x 106 cells/kg when administered after an immune selective PC regimen. Ongoing efforts are further evaluating the combination of PC chemotherapy followed by T1-Rapa cell therapy (5 x 106 cells/kg dose).Table 1Autologous T-Rapa Cell Therapy of Multiple MyelomaUPN #T1-Rapa Dose1PC RegimenDisease Progression2Ongoing CR11 x 105/kg-31725 x 105/kg-27331 x 106/kg-68843 x 106/kg-12253 x 106/kg-+ 118665 x 106/kg-66475 x 106/kg-10085 x 106/kg-91795 x 106/kg-NE105 x 106/kg-246115 x 106/kg-+ 926125 x 106/kg-1521315 x 106/kg-4221415 x 106/kg-+ 8471515 x 106/kg-641615 x 106/kg-4221715 x 106/kg-18818#1: 5 x 106/kg#2: 5 x 106/kg-7-day PC66819#1: 5 x 106/kg#2: 5 x 106/kg-7-day PC+ 73320#1: 5 x 106/kg#2: 5 x 106/kg-7-day PC+ 7871 The final cohort received T1-Rapa cells alone (cycle #1) and then after the PC regimen (cycle #2), with at least one month separating the cycles.2 Disease progression or ongoing CR: number of days post auto-HSCT; NE, not evaluable (lost to follow-up). Open table in a new tab