Treatment duration with immune-based therapies in Cancer: an enigma

Abstract

Unlike chemotherapy treatments that target the tumor itself (rather nonspecifically), immune-based therapies attempt to harness the power of an individual patient's immune system to combat cancer. Similar to chemotherapeutic agents, the dosage and Administration section of labeling for all five currently approved PD-1/PD-L1 inhibitors (immunotherapy) recommends duration of treatment until disease progression or unacceptable toxicity. Overactivation or constitutive activation of the immune system with immune based therapies can lead to T-cell exhaustion and activation induced cell death (AICD) in T- and B-cells. Examples of immune exhaustion and T-cell depletion is noted in preclinical and clinical studies. Overactivation or constitutive activation leading to Immune exhaustion is a real phenomenon and of profound concern as immune cells are the true arsenal for control of the tumor growth. Designing trials rigorously to address the optimum treatment duration with immune based therapies is critical. By addressing this concern now, not only we may improve patient outcomes, but also gather a deeper understanding of the role and mechanisms of the immune system in the control of tumor growth.Chemotherapy and immune-based therapies provide antitumor effects through completely different mechanisms. Chemotherapeutic agents are cytotoxic in that they directly inhibit basic cellular mechanisms, killing both malignant and nonmalignant cells (hopefully with a preference for malignant cells), while immune based therapies wake-up the host immune system to recognize malignant cells and eliminate them.While there is a burgeoning excitement surrounding development of immune based therapies for the treatment of cancer, the optimal duration for these therapies need to be explored with equal fervor. Dosing for chemotherapy has been determined over years through large-scale prospective randomized trials to pinpoint the dose which maximizes therapeutic effect while minimizing side effects. Also, due to the mechanism of chemotherapeutic action, the duration of treatment with these agents is generally until disease progression or patient intolerance. However, experience with immune based therapies is limited, with current dosing and duration guidelines based primarily on initial trials required for approval of the agents. Since immune based therapies work by activating the body's own immune system, there is concern that overactivation or constitutive activation of the immune system may lead to immune exhaustion and depletion of effector T-cells thereby causing decreased anti-tumor effects and possible allowing for tumor progression.Similar to chemotherapeutic agents, the Dosage and Administration section of labeling for all five currently approved PD-1/PD-L1 inhibitors recommends duration of treatment until disease progression or unacceptable toxicity. However, since immune based therapies work with a completely different mechanism compared to chemotherapy, using the same therapy duration may not be the optimal approach.In exploring treatment duration with immune based therapies, we need to answer the following: (1) does indefinite treatment with immune based therapies exhaust the immune system counteracting its own mechanism of action leading to tumor progression and (2) how can clinical trials be designed to identify the optimal duration of immune-based therapy that prevents immune cell exhaustion but supports anti-tumor immunity.

Keywords: Immune exhaustion; Immunotherapy; Treatment duration.

Fig. 1

Elevation of guanosine with PNP inhibition causes immune activation through TLRs