Chemotherapy Combines Effectively with Anti–PD-L1 Treatment and Can Augment Antitumor Responses

Abstract

Immunotherapy with checkpoint inhibitors has proved to be highly effective, with durable responses in a subset of patients. Given their encouraging clinical activity, checkpoint inhibitors are increasingly being tested in clinical trials in combination with chemotherapy. In many instances, there is little understanding of how chemotherapy might influence the quality of the immune response generated by checkpoint inhibitors. In this study, we evaluated the impact of chemotherapy alone or in combination with anti-PD-L1 in a responsive syngeneic tumor model. Although multiple classes of chemotherapy treatment reduced immune cell numbers and activity in peripheral tissues, chemotherapy did not antagonize but in many cases augmented the antitumor activity mediated by anti-PD-L1. This dichotomy between the detrimental effects in peripheral tissues and enhanced antitumor activity was largely explained by the reduced dependence on incoming cells for antitumor efficacy in already established tumors. The effects of the various chemotherapies were also agent specific, and synergy with anti-PD-L1 was achieved by different mechanisms that ultimately helped establish a new threshold for response. These results rationalize the combination of chemotherapy with immunotherapy and suggest that, despite the negative systemic effects of chemotherapy, effective combinations can be obtained through distinct mechanisms acting within the tumor.

Immune Checkpoint Blockade Improves Chemotherapy in the PyMT Mammary Carcinoma Mouse Model

“…Indeed, our study showed an enhanced efficacy of anti-PD-1 administration plus DOX chemotherapy in reducing the growth in PyMT tumors compared to monotherapy. In line with our findings, preclinical studies demonstrated the efficacy of anti-PD-(L)1 plus different chemotherapy agents in murine colon and lung adenocarcinoma models (41,42). Interestingly, a recent clinical phase 3 study (IMpassion130) assessing the efficacy and safety of atezolizumab (anti-PD-L1 antibody) plus nab-paclitaxel (chemotherapy) in patients with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC) reported a clinically meaningful overall survival benefit with chemoimmunotherapy in patients with PD-L1 immune cell-positive disease (43).…”

Cytotoxic Chemotherapy as an Immune Stimulus: A Molecular Perspective on Turning Up the Immunological Heat on Cancer

“…There is evidence that CCTs can selectively target immune suppressive cell populations, for example preferential depletion of Tregs in response to paclitaxel (82), cyclophosphamide (83), or temozolomide (84) treatment. MDSCs have been shown to be preferentially depleted by doxorubicin (85, 86) and 5-FU (85), and TAMs by gemcitabine (9). CCTs can also activate NK cells (87), but also concurrently render tumor cells more susceptible to NK cell-mediated lysis, such as through promoting the expression of B7-H6, the ligand for the NK cell activating receptor NKp30, on the tumor cell surface (88).…”

Checkpoint Blockade Treatment May Sensitize Hodgkin Lymphoma to Subsequent Therapy

“…Checkpoint blockers remain active systemically for several months beyond the time of administration owing to a half-life of 15-25 days [23-25]; side effects of CBT have been seen up to a year after discontinuation [26]. Murine studies suggest that chemotherapy increases the antitumor activity mediated by CBT by inducing immunological changes, which vary depending on the chemotherapeutic agent used [27]. In lung cancer and renal cell carcinoma, the addition of immunotherapy to chemotherapy and targeted agents has shown superior results to chemotherapy alone [28,29].…”