The Most Effective Self-Sustaining Antitumor Responses Activated by anti-PD1 Antibody are Likely Mediated by PD1-Negative T Cells

Abstract

Kangla Tsung, Zhang Xu and Zhang Hui and TANLUN Clinical Research Participant Group

Immune checkpoint inhibitor (ICI) therapy has transformed the battlefield of cancer therapy by showing some of the most dramatic and durable antitumor responses ever seen. Yet ICI therapy is only effective in a minority of cancer patients. Among responders, only a few of them demonstrated a durable and self-sustaining pattern of response. It would be desirable to repeat the most durable success of ICI therapy in as more cancer patients as possible. That requires the true understanding of the mechanism behind the therapy. In previous publication, we have pointed out that the current blocking model of how ICI ther- apy works is wrong in that it cannot explain some critical observations such as the trigger effect, the hyper-progression and the autoimmunity associated with the therapy. On the other hand, we have raised an alternative model based on the partial depletion of PD1-positive T cells and the subsequent homeostatic activation of remaining T cells. This model, which we call the depletion model, could explains all of the perplexing clinical observations mentioned above. It also predicts that under repeated administration of antibodies to PD1/PDL1, a common practice in the clinic, the surviving immune response must be mediated by PD1-nagative T cells. Since some of the most dramatic and durable responses to ICI therapy did not require antigen-releasing treatments (such a chemotherapy), they must be self-sustaining as well. Here, using real-world cases, we present evidence that the most effective and self-sustaining antitumor responses are likely mediated by PD1-nagative T cells, an observation supporting our depletion model for ICI therapy. This observation raises fundamental questions regarding the current clinical use of ICI therapy and points to a future direction for the search of ways to activate PD1-nagative T cells for antitumor response.

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