Targeting Lymphomas Using Non-Engineered, Multi-Antigen-Specific T Cells

Immunotherapy is emerging as a potent treatment for a range of hematologic malignancies including lymphomas. Indeed adoptive transfer of T cells genetically engineered to express the CD19 CAR has now received FDA approval for the treatment of refractory diffuse large B cell lymphomas (DLBCL). We have developed a non-engineered T cell therapy to treat patients with Hodgkin's and non-Hodgkin's lymphoma (HL/NHL) using single T cell lines that simultaneously target the tumor-associated antigens (TAAs) PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin. We can consistently prepare these lines by culturing PBMCs in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail, and adding autologous pepmix-loaded DCs as APCs. The use of whole antigen overcomes the HLA restriction imposed by the use of transgenic TCRs specific for single peptides, while targeting multiple antigens simultaneously should reduce the risk of tumor immune evasion. We have generated 42 clinical-grade multiTAA T cell lines, comprising CD3+ T cells (mean 98±1.1%) with a mixture of CD4+ (mean 48±4.3%) and CD8+ (mean 37±4%) T cells that recognize the targeted antigens PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin (range 0-463, 0-496, 0-330, 0-379 and 0-304 SFU/2 × 10 5 , respectively in IFNg ELIspot). None of the lines reacted against non-malignant autologous cells (3±3.8% specific lysis; E:T 20:1). We have treated 33 patients: 13 with HL, 17 with aggressive NHL (DLBCL, mantle cell, T cell lymphomas) and 3 with indolent NHLs (FL, marginal zone lymphoma). Patients were infused with 0.5-2 × 10 7 multiTAA-T cells/m 2 and did not receive lymphodepleting chemotherapy. Of 18 patients who were infused as adjuvant all but 2 remain in remission (range 3-42 months). Fifteen patients have received multiTAA-specific T cells to treat active disease, all of whom had failed a median of 4 lines of prior therapy. Of these, 5 had transient disease stabilization followed by disease progression, 4 have ongoing stable disease at 3-18 months post-multiTAA-specific T cells while the remaining 6 (3 with HL and 3 with DLBCL) had complete and durable responses (4 to 41 months), as assessed by PET. These clinical responses correlated with the detection of tumor-reactive T cells in patient peripheral blood post-infusion directed against both targeted antigens as well as non-targeted TAAs including MAGEA2B and MAGE C1, indicating induction of antigen/epitope spreading. Notably, no patient, including the complete responders, had infusion-related systemic- or neuro-toxicity. Thus, infusion of autologous multiTAA-targeted T cells directed to PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin has been safe, and despite concerns that endogenous T cells directed against shared/cancer testis antigens would be of insufficient affinity to produce prolonged benefit our multiTAA-specific T cells were able to induce durable complete responses in patients with lymphomas.