This clinical trial evaluates autologous rapamycin-resistant Th1/Tc1 (RAPA-201) cells for therapy of relapsed, refractory multiple myeloma (RRMM). The study population of RRMM patients is defined by: relapse after ≥ 3 prior regimens; exposure to ≥ 2 proteasome inhibitors (PI) (e.g. bortezomib), ≥ 2 immunomodulatory agents (IMiD) (e.g. lenalidomide), and ≥ 1 anti-CD38 monoclonal antibody (e.g., daratumumab); and refractory status to ≥ 1 PI agent and ≥ 1 IMiD agent. The primary study objective is to determine the overall response rate, as evaluated by IMWG criteria, of RAPA-201 cells and a pentostatin-cyclophosphamide (PC) host conditioning regimen in patients with RRMM. A sample size of 22 patients was selected to determine whether RAPA-201 therapy represents an active regimen in RRMM, as defined by a response rate (≥ partial remission) consistent with a 35% rate.

Multiple myeloma (MM) is an incurable cancer characterized by clonal proliferation of plasma cells. MM is the second most common form of hematologic malignancy in the United States, with approximately 11,000 individuals dying from the disease in 2014. Due in part to the aging population, MM prevalence will dramatically increase in the next few decades. MM management has many FDA-approved options for the up-front setting, maintenance therapy, and therapy at second or third relapse. For patients with relapsed MM, therapy typically consists of triplet regimens approved by the U.S. Food and Drug Administration (FDA), including the KRd, DRd, and DPd regimens. Although triplet regimens are improved relative to prior therapies, they typically provide a progression-free survival of less than two years and cause substantial toxicities. Few standard, effective options exist for patients with MM who have more advanced disease and higher levels of drug refractoriness. In contrast to drug and monoclonal antibody therapy, which are essentially non-curative, T cell therapy can cure MM, as evidenced by long- term survival in recipients of allogeneic hematopoietic cell transplantation. The promise of T cell therapy against MM is further exemplified by high response rates using gene-modified autologous CAR-T cell therapy directed against the BCMA target. However, CAR-T therapy is limited by variable tumor cell target expression, which compromises response durability leading to relapse. Furthermore, CAR-T cell products are expensive to manufacture, with the financial burden further complicated by frequent inpatient hospital monitoring and treatment of potentially lethal toxicities that include cytokine storm and neurologic damage. Thus, a great need exists to develop novel T cell therapies for RRMM that are safe, cost effective, and curative. We will evaluate one such promising candidate, namely, autologous rapamycin-resistant Th1/Tc1 cells (RAPA-201).

RAPA-201 cell therapy differs from existing approaches in several important categories. First, RAPA-201 cells are rendered rapamycin-resistant by proprietary ex vivo manufacturing that rapidly and cost effectively de- differentiates senescent patient T cells, which results in a therapeutic product enriched for the beneficial T central memory (TCM) subset and severely depleted of checkpoint inhibitory receptors that inhibit anti-cancer effects. This depth and breadth of T cell re-programming is not possible in vivo due to toxicity of pharmacologic agents, which can be rendered completely non-toxic through drug extracorporealization. Operating together, T cell rapamycin-resistance, TCM differentiation, and checkpoint removal promotes RAPA-201 T cell in vivo persistence and in vivo activity required for curative anti-tumor effects. Second, RAPA-201 cells are manufactured in a high, otherwise toxic dose of the critical anti-cancer cytokine IFN-α, which promotes a CD4+Th1 and CD8+Tc1 T cell phenotype that optimizes anti-tumor effects. Third, rapamycin-resistant T cells express a diverse T cell receptor repertoire that can address the complex biology of multiple myeloma, where tumor antigens are either not known or variable over time due to tumor genetic instability. Because polyclonal RAPA-201 T cells are capable of in vivo expansion to tumor antigens, RAPA-201 therapy can be applied not only to RRMM but also to other hematologic malignancies and common solid tumors, including lung cancer resistant to PD(L)-1 checkpoint therapy. And fourth, RAPA-201 cell therapy will be administered in combination with a novel host conditioning regimen consisting of pentostatin and low-dose, dose-adjusted cyclophosphamide (PC regimen). The PC regimen causes host lymphoid depletion while sparing host myeloid cells, thus permitting repeat therapeutic RAPA-201 cycles in the outpatient setting with reduced financial burden and without substantial neutropenia and associated opportunistic infection. As such, the PC regimen safely creates "immune space" in the RRMM patient, thereby potentiating the in vivo expansion and curative potential of RAPA-201 cells.