In situ immunization

Abstract

The arming of activated T cells (ATC) with BiAbs can overcome major barriers for successful adoptive immunotherapy. The BiAb approach takes the advantage of the targeting specificity of monoclonal antibodies and the cytotoxic capacity of T cells to lyse tumors. Arming of ATC with BiAb makes every T cell an antigen-specific CTL and infusions of such cells will markedly increase the effective precursor frequency of CTL in the cancer patient. Furthermore, the ability of such armed ATC to kill multiple times without rearming with BiAb, secrete tumoricidal cytokines, secrete chemokines, and survive in patients for up to 8 days after the last infusion or in Beige/SCID mice for over 13 weeks after cessation of treatment. The persistence of cells in the Beige/SCID after infusion show long-term survival capability in the host. Re-stimulation of armed ATC after 3 cycles of cytotoxicity with tumor cells resulted in the secretion of interferon gamma indicating the development of tumor specific immune responses in the population of cells that have been exposed multiple times to antigen. In summary, armed ATC can act as a cytotoxic 'drug', kill multiple times (direct killing), divide after killing (increasing the effector:target ratio in vivo), secrete tumoricidal cytokines (indirectly killing), secrete chemokines at the tumor site (recruit naïve T cells and antigen-presenting cells to immunize the patient to tumor lysate) and persist in patients and animal models for weeks to months (long-term survival).