Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy
Posted: Sat Jul 29, 2017 11:08 pm
Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy
Abstract
With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade
Conclusions and future biomarker considerations
Recent clinical advances with drugs that block immune checkpoints have brought immunotherapy out of the realm of highly specialized therapy and into the mainstream of oncology. To date, anti-CTLA4 therapy has shown reproducible activity only in patients with advanced melanoma. In contrast, anti-PD1–PDL1 drugs blocking a related but distinct immune checkpoint seem to have a broad range of activity extending beyond melanoma to an expanding list of cancers, including those of the lung, kidney, bladder, head and neck, breast, liver and gastrointestinal tract, and certain lymphoma subtypes. However, other cancer types such as prostate cancer and CRC have proved much more resistant to anti-PD1 therapies, underscoring the need for biomarker development. The evolution of our basic mechanistic understanding of immune checkpoint pathways has facilitated the search for pretreatment and on-treatment biomarkers that predict clinical response in different tumour types and the individual patients associated with them. The functional attributes of CTLA4, PD1 and other immune checkpoints will guide future biomarker discovery strategies uniquely suited to these non-redundant regulatory pathways. The predominant impact of the PD1 pathway in peripheral tissues suggests that the tumour site itself contains the most important clues for the development of anti-PD1 therapy biomarkers; in fact, this has been a rich source of promising biomarker leads pertaining to the expression of immunoregulatory molecules, oncogenic driver mutations, mutational burden and cancer-associated viruses. In contrast, the global inhibitory effects of CTLA4 in the immune system are consistent with systemic pharmacodynamic alterations found in circulating lymphocytes.
Whereas CTLA4 and PD1 blockade have reached the stage of regulatory approval, the list of additional checkpoint receptors and ligands being targeted clinically is growing. Examples include LAG3, T-cell immunoglobulin mucin receptor 3 (TIM3; also known as HAVCR2), B7H3 (also known as CD276), CD39, CD73 and the adenosine A2a receptor113–117. Inhibitory metabolic enzymes, such as IDO1, are also being targeted by small molecules118. Most of these immune checkpoints are being targeted in conjunction with PD1 pathway blocking antibodies. As mentioned above, some of these checkpoints are co-expressed with PDL1, providing a rationale for this dual blockade therapy. However, because clinical trials are in their early stages, there are as yet no validated biomarkers to predict which patients will benefit most from dual blockade of these molecules. Although several trials involve analysis of expression of the target in tumour biopsies, it is not yet clear which of these operate predominantly within the TME compared with outside the TME, that is, during T cell activation within lymph nodes. Nonetheless, intensive pharmacodynamic and correlative immune studies will be needed as part of all early-stage clinical trials — this is the only way that biomarker candidates can be identified as combinatorial checkpoint blockade approaches proliferate.
As more is learned about the TME and about regulation of systemic immunity to cancer, it is likely that additional biomarkers will emerge. For example, recent studies on metabolism demonstrate that tumours and T cells compete for glucose and that this competition can affect the glycolysis-dependent function of TILs119, raising the notion that metabolic biomarkers may be crucial factors in antitumour responsiveness. Another potential biomarker is the gut microbiome. Two recent studies speak to this possibility. One study in mice suggested that microbiomes high in Bifidobacter species enhanced tumour response to anti-PDL1 therapy120. A study in humans suggested that Bacteroides species (Bacteroides fragilis and Bacteroides thetaiotaomicron) in the microbiome might enhance the response of patients with melanoma to anti-CTLA4 therapy121. Even though the mechanisms by which these species may enhance systemic antitumour immunity are unknown at this time, these data suggest that microbiome-derived biomarkers may be developed to guide immunotherapy.
Unlike static biomarkers defined by driver mutations directly linked to the activity of targeted kinase inhibitors, the ever-changing immune system poses unique challenges to biomarker development. However, it is the adaptability of the immune system that also underlies its vast potential to keep pace with cancer evolution and provide durable treatment responses that are not achievable with most other forms of cancer therapy.
https://www.ncbi.nlm.nih.gov/pmc/articl ... n_sectitle
Abstract
With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade
Conclusions and future biomarker considerations
Recent clinical advances with drugs that block immune checkpoints have brought immunotherapy out of the realm of highly specialized therapy and into the mainstream of oncology. To date, anti-CTLA4 therapy has shown reproducible activity only in patients with advanced melanoma. In contrast, anti-PD1–PDL1 drugs blocking a related but distinct immune checkpoint seem to have a broad range of activity extending beyond melanoma to an expanding list of cancers, including those of the lung, kidney, bladder, head and neck, breast, liver and gastrointestinal tract, and certain lymphoma subtypes. However, other cancer types such as prostate cancer and CRC have proved much more resistant to anti-PD1 therapies, underscoring the need for biomarker development. The evolution of our basic mechanistic understanding of immune checkpoint pathways has facilitated the search for pretreatment and on-treatment biomarkers that predict clinical response in different tumour types and the individual patients associated with them. The functional attributes of CTLA4, PD1 and other immune checkpoints will guide future biomarker discovery strategies uniquely suited to these non-redundant regulatory pathways. The predominant impact of the PD1 pathway in peripheral tissues suggests that the tumour site itself contains the most important clues for the development of anti-PD1 therapy biomarkers; in fact, this has been a rich source of promising biomarker leads pertaining to the expression of immunoregulatory molecules, oncogenic driver mutations, mutational burden and cancer-associated viruses. In contrast, the global inhibitory effects of CTLA4 in the immune system are consistent with systemic pharmacodynamic alterations found in circulating lymphocytes.
Whereas CTLA4 and PD1 blockade have reached the stage of regulatory approval, the list of additional checkpoint receptors and ligands being targeted clinically is growing. Examples include LAG3, T-cell immunoglobulin mucin receptor 3 (TIM3; also known as HAVCR2), B7H3 (also known as CD276), CD39, CD73 and the adenosine A2a receptor113–117. Inhibitory metabolic enzymes, such as IDO1, are also being targeted by small molecules118. Most of these immune checkpoints are being targeted in conjunction with PD1 pathway blocking antibodies. As mentioned above, some of these checkpoints are co-expressed with PDL1, providing a rationale for this dual blockade therapy. However, because clinical trials are in their early stages, there are as yet no validated biomarkers to predict which patients will benefit most from dual blockade of these molecules. Although several trials involve analysis of expression of the target in tumour biopsies, it is not yet clear which of these operate predominantly within the TME compared with outside the TME, that is, during T cell activation within lymph nodes. Nonetheless, intensive pharmacodynamic and correlative immune studies will be needed as part of all early-stage clinical trials — this is the only way that biomarker candidates can be identified as combinatorial checkpoint blockade approaches proliferate.
As more is learned about the TME and about regulation of systemic immunity to cancer, it is likely that additional biomarkers will emerge. For example, recent studies on metabolism demonstrate that tumours and T cells compete for glucose and that this competition can affect the glycolysis-dependent function of TILs119, raising the notion that metabolic biomarkers may be crucial factors in antitumour responsiveness. Another potential biomarker is the gut microbiome. Two recent studies speak to this possibility. One study in mice suggested that microbiomes high in Bifidobacter species enhanced tumour response to anti-PDL1 therapy120. A study in humans suggested that Bacteroides species (Bacteroides fragilis and Bacteroides thetaiotaomicron) in the microbiome might enhance the response of patients with melanoma to anti-CTLA4 therapy121. Even though the mechanisms by which these species may enhance systemic antitumour immunity are unknown at this time, these data suggest that microbiome-derived biomarkers may be developed to guide immunotherapy.
Unlike static biomarkers defined by driver mutations directly linked to the activity of targeted kinase inhibitors, the ever-changing immune system poses unique challenges to biomarker development. However, it is the adaptability of the immune system that also underlies its vast potential to keep pace with cancer evolution and provide durable treatment responses that are not achievable with most other forms of cancer therapy.
https://www.ncbi.nlm.nih.gov/pmc/articl ... n_sectitle