Adoptive transfer of gene-modified T-cells engineered to express high-affinity tcr's for cancer-testis antigens NY-ESO-1 or lage-1, in multiple myeloma (MM) patients post autologous hematopoietic stem cell transplant (ASCT)

      Adoptive immunotherapy for cancer has been limited by poor antigen specificity, low target antigen expression, and self-tolerance. We hypothesized that genetic engineering of autologous T cells with affinity-enhanced tumor antigen-specific T cell receptors (TCRs) and ex vivo CD3/CD28 costimulation may overcome these limitations. We are conducting a clinical trial (NCT01352286) evaluating T cells engineered with an HLA-A0201 restricted, affinity-enhanced TCR that recognizes an epitope expressed by NY-ESO-1 and LAGE-1 tumor antigens (TCR-T). TCR-T are infused in the setting of profound lymphodepletion that accompanies high-dose chemotherapy followed by aSCT in patients with high risk or relapsed multiple myeloma (MM). TCR-T are manufactured from an apheresis product depleted of monocytes and CD25+ cells, gene-modified by lentivector, and expanded using microbead-based CD3/CD28 costimulation. 15 patients have been infused. 11 more are planned. An average of 8.5 × 109 TCR-T, with transduction efficiency averaging 33%, was administered per patient. 15, 13, and 10 patients have reached the day 42, 100 and 180 MM assessment time points, respectively. At day 100, 10/13 (77%) patients have a best response of VGPR or better and 3/13 (23%) have partial responses. 5 patients have progressed after day 100 and 10 continue to respond to therapy. These results are especially encouraging since 4/15 patients had prior aSCT and 8/15 had high risk cytogenetics. TCR-T expanded through day 14, and persisted in all patients through day 180 and to levels up to 1% at 1yr in blood and marrow by flow cytometry. Patients with progressive disease showed low levels or loss of TCR-T, or loss of target tumor antigen at time of progression, suggesting specific activity of TCR-T. This is the first test of TCR-T in the MM setting, which indicates it is well tolerated and associated with encouraging response rates.
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