T Cell Blockade Immunotherapy Against Cancer and Abscopal Effect in Combination Therapy

Abstract

Stereotactic ablative body radiotherapy (SABR) has been described to induce abscopal effects. The “abscopal effect” is the occurrence of objective tumour regressions induced following irradiation at sites outside the irradiated field. However, this effect is limited and occurs in about 5 % of patients. This phenomenon has been reported in various tumour forms but mainly as singular events. Recent evidence that radiation induces immunogenic tumour cell death and alters the tumour microenvironment to enhance recruitment of antitumor T cells supports the hypothesis that radiation can enhance both the priming and the effector-phase of the antitumor immune response. SABR treatment of inoperable renal cancer results in local tumour sterilization with release of tumour cell fragments containing molecules that may be immunogenic. For instance, apoptosis and necroptosis, forms of cell death, have recently been demonstrated to be immunogenic if induced by drugs like anthracyclines or by ionizing radiation. These tumour antigens are taken up locally and systemically by antigen presenting cells, particularly the dendritic cells (DC), which have the potential to stimulate de novo production of specific immune responses. Cells and molecules, however, regulate anti-tumoral immuneresponse, with the ability to inhibit particularly response to “self” tumour antigens. The intervention at the checkpoint level through the administration of anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibodies or anti-programmed cell death protein 1 (PD-1) can arrest these immune regulatory mechanisms, resulting in activation of the anti-tumour responses to the antigens released by SABR, and thus acting in synergy with SABR. Additional activation of anti-tumour immunity can also be obtained by administration of autologous DC “pulsed” ex vivo, with tumour-derived material; adoptively transfer tumour specific T cells, derived either from Tumour Infiltrating T cells (TIL) or from autologous T cells retrovirally transduced with tumour specific T cell receptors (TCRs).