About this Research Topic
Immune checkpoint blockade (ICB) as a treatment of cancer has been an ongoing hot topic for several years now. There has been much success in clinical trials with immune checkpoint blocking antibodies targeting PD-1/PD-L1 and/or CTLA-4 in several tumor types, and approaches targeting multiple immune checkpoints are showing success.
However, a substantial fraction of patients still do not achieve a response to ICB. Recent reports from clinical trials with the longest follow up after ICB in melanoma and lung cancer indicate that patients achieving a clinical response early upon treatment are more likely to experience long term survival. Hence, there is a critical need to understand the molecular determinants of tumor responses to ICB for improving patients management as well as the design of more effective combinatorial approaches based on new rational targets. Many preclinical and clinical studies have been investigating the therapeutic potential of targeting immune checkpoint molecules in combination with other immunotherapies, molecular targeted therapies, or standard anti-cancer treatments. Insights into the biological mechanisms underlying the activity of these combination therapies have, however, lagged significantly behind.
Cytotoxic chemotherapy and targeted therapies with small molecules inhibitors of critical pro-tumorigenic pathways can produce rapid tumor responses, however, these responses are very often short-lived, especially with targeted therapies, but they can be administered more frequently. The rational combination of these treatments with ICB offers promise, as on the one hand, it can facilitate rapid achievement of responses, which is a prerequisite for the long-lasting clinical benefit of immunotherapy, and, on the other, it would allow for immune-mediated consolidation of anti-tumor effects, thus leading to sustained therapeutic activity. Deepening our understanding of the mechanisms underlying activity of these ICB-based combinations will aid in the clinical development of novel and more efficacious treatments.
In this Research Topic, we would like to highlight the mechanisms behind the long-lasting anti-tumor activity of immunotherapeutic approaches that incorporate ICB to treat cancer. This includes mechanistic studies of ICB in combination with small molecule inhibitors of pro-tumorigenic pathways (targeting tumor-intrinsic oncogenic signaling cascades, critical metabolic pathways, or tumor-extrinsic pathways, such as tumor angiogenesis and mechanisms for metastatic dissemination). We are particularly interested in studies investigating the molecular determinants of long-term effects of ICB, such as the mechanisms leading to long-lasting immunological memory responses upon ICB. Discussion should integrate published results and original findings, allowing for new hypothesis generation while highlighting potential drawbacks.
We welcome the submission of Original Research Articles, Reviews, and Mini Reviews, which cover, but are not limited to, the following topics:
• Mechanisms that determine the durability of tumor responses to ICB-based therapies;
• Mechanistic factors that predict outcome (both positive and negative) of these treatments;
• Effects of ICB on anti-tumor immunological memory responses and long-term effects.
Topic Editor Dr. Taylor receives financial support from Actuate Therapeutics.
Keywords: Cancer immunotherapy, immune checkpoint blockade, immunological memory, small molecule inhibitors, immunotherapy resistance
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