New Combination Strategies Using Programmed Cell Death 1/Programmed Cell Death Ligand 1 Checkpoint Inhibitors as a Backbone

Abstract

The discovery of immune checkpoints and subsequent clinical development of checkpoint inhibitors has revolutionized the field of oncology. The durability of the anti-tumor immune responses has raised the hope for long term patient survival and potential cure; however, currently only a minority of patients respond. Combination strategies to help increase antigen release and T cell priming, promote T cell activation and homing, improve the tumor immune microenvironment, all guided by predictive biomarkers, can help overcome the tumor immune-evasive mechanisms and maximize efficacy to ultimately benefit the majority of patients. Great challenges remain due to the complex underlying biology, unpredictable toxicity and accurate assessment of response. Carefully designed clinical trials guided by translational studies of paired biopsies will be key to develop reliable predictive biomarkers to choose which patients would most likely benefit from each strategy.

Anti-PD-1 Therapy plus Chemotherapy and/or Bevacizumab as Second Line or later Treatment for Patients with Advanced Non-Small Cell Lung Cancer

“…Increasing evidences indicated that additional treatments up-regulating the release and presentation of tumor-specific neoantigen would synergize with ICIs, such as chemotherapy and radiotherapy. 15,16 In addition, angiogenesis inhibitors could also synergistically act with ICIs by modulating tumor microenvironment and promoting immune cell infiltration. 17,18 As such, a number of clinical trials were conducted to investigate whether ICIs combination therapy is effective as first-line treatment in aNSCLC.…”

Simplified Admix Archaeal Glycolipid Adjuvanted Vaccine and Checkpoint Inhibitor Therapy Combination Enhances Protection from Murine Melanoma

“…Archaeal lipid adjuvants are a good potential candidate for use in combination with CPI's, as evidenced by their proven safety and efficacy in mice [19,44]. In multiple pre-clinical studies, they have been shown to activate antigen-specific CD8 + T cell responses [15,19,26,27] and generate protective immunity in tumor models, e.g., B16-OVA melanoma [7,13,19,23,26,27], and against multiple infectious diseases, e.g., H1N1 influenza [11], Listeria monocytogenes [7,12], Trypanosoma cruzi [13] and Mycobacterium tuberculosis [14].…”

Intralesional interleukin‐2: A novel option to maximize response to systemic immune checkpoint therapy in loco‐regional metastatic melanoma

“…The combination of local and systemic immunotherapy holds promise as a novel treatment strategy, and may even form the “backbone” of future treatment (Hu‐Lieskovan & Ribas, ). Not only were we able to achieve lasting local disease control in the injected lesions in both patients, but immunohistochemical examination of the metastases demonstrated increased PD‐L1 expression and CD8+ T cell infiltration.…”

“…In fact, the combination of both local and systemic immunotherapy has become an important research focus, with the aim of altering the tumor microenvironment to improve overall response to treatment (Hu‐Lieskovan & Ribas, ). For example, combination of oncolytic virotherapy with anti‐PD‐1 systemic therapy increases intratumoral T cell infiltration and PD‐L1 expression, associated with improved response to systemic treatment (Ribas et al, ).…”