Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy

Abstract

SUMMARY Checkpoint blockade immunotherapies can be extraordinarily effective, but may benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when using appropriately selected immunogenic drugs (e.g. oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53). The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8+ T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

“…31 The induction of immunogenic conditions in the TME with an immunogenic chemotherapy or radiation therapy is thought to convert immunologically “cold” tumors into “hot” tumors via release of tumor neoantigens. 32,33 Similarly, the pushing of tumor cells toward immunogenic death by SGT-53 may be quite effective in promoting in tumor elimination by the immune system.…”

Role of vascular normalization in benefit from metronomic chemotherapy

“…Furthermore, assuming that vascular normalization did not occur in metronomic chemotherapy, the efficacy of treatment would be better than that of MTD owing to reduced immunogenic cell death and the decreased number of Tregs as a result of metronomic dose scheduling (SI Appendix, Fig. S12) (41).…”

Heating it up: Oncolytic viruses make tumors ‘hot’ and suitable for checkpoint blockade immunotherapies

“…14 , 15 Similarly, it has been shown that immunogenic cell death (ICD) inducers such as oxaliplatin and cyclophosphamide sensitize KRAS-induced lung cancers to subsequent immune checkpoint blockade. 16 It is not unreasonable to postulate that viruses, in particular T-VEC, can induce ICD because T-VEC has been genetically modified to remove genes that suppress the immune response and accentuate the premortem stress responses, including the type-1 interferon response, that characterize ICD. 17-22 These emerging studies emphasize the need to rationally design for combination immunotherapies with respect to timing and dosing.…”