Potential elimination of multi-drug resistant cancer cells by targeted non-engrafting intentionally mismatched activated donor lymphocytes.

Abstract

e14007 Background: Immunotherapy by targeted autologous T cells, TIL or CAR-T, are considered most effective modalities for treatment of otherwise resistant cancer, yet cure is rarely achieved. In contrast, cure of resistant disease by donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation suggests that alloreactive lymphocytes represent a most effective approach for elimination of resistant malignant cells. The first patient relapsing following supra-lethal chemoradiotherapy is alive & well > 34 years. Using murine B cell leukemia (BCL1) and metastatic breast cancer (4T1) we proved that non-engrafting intentionally mismatched lymphocytes activated with IL-2 that were consistently rejected cured otherwise lethal cancer with no graft-vs-host disease (GVHD). Methods: We first applied graft-vs-tumor effects by non-engrafting Intentionally Mismatched Activated Killers (IMAK) following mild immunosuppressive conditioning to maximize homeostatic proliferation of activated T & NK cells. IMAK was first applied inpatients with multiple myeloma and lymphoma treated with donor lymphocytes pre-activated in vitro prior to infusion and for 5 days following infusion withlow dose IL-2.We next studied feasibility of Allogeneic Targeted Activated Cancer Killer cells (ATACK) using IL-2 activated haploidentical donor lymphocytes including T & NK cells targeted against antigens over-expressed on the surface of malignant cells: Her-2/neu, EGFR, VEGF and CD20 using commercially available Herceptin, Erbitux, Avastin or Rituximab, respectivelyin a pilot study involving 16 patients with advanced metastatic solid tumors. Results: Using IMAK donor lymphocytes were uniformly rejected and no patient developed GVHD. Disease-free survival > 20 years was documented in our first myeloma patient with plasmacytomas and in another relapsing after autologous SCTand in 2 patients with non-Hodgkin lymphoma. Longterm progression-free survival was reported in 5 of 31 patients with resistant solid tumors. Following ATACK transient mild toxicity was manageable in outpatient clinic and no GVHD developed. Conclusions: Using ATACK against minimal residual disease accomplishable by most cancer patients following conventional 1st line treatment may result in cure of otherwise resistant cancer while avoiding GVHD.