- Email: [email protected]
Immune checkpoint inhibitors: a perspective of established and potential combination therapy
Annals of Oncology 30 (Supplement 6): vi33, 2019 doi:10.1093/annonc/mdz326
SYMPOSIUM 7 : FUTURE PROSPECTS OF IMMUNE CHECKPOINT INHIBITORS TUMOR AND HOST FACTORS REGULATING ANTI-TUMOR IMMUNITY AND IMMUNOTHERAPY EFFICACY
Thomas Gajewski University of Chicago, United States Characterization of the "T cell-inflamed" and "non-T cell-inflamed" tumor microenvironments has generated a framework for identifying immunotherapeutic targets and for understanding mechanisms of efficacy versus resistance. The T cell-inflamed phenotype includes expression of chemokines, T cell markers, and a type I IFN signature, whereas the non-T cell-inflamed phenotype lacks these factors and appears to display immune "exclusion". The mechanisms of immune escape are likely distinct in these two subsets, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3þ Tregs. Deep analysis of tumor antigen-specific T cells in the tumor microenvironment has identified additional mechanisms of immune dysfunction and new potential therapeutic targets, beyond PD-1. In contrast to the T cell-inflamed tumors, non-T cell-inflamed tumors are largely immunotherapy resistant with current approaches. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via Batf3-lineage DCs. New strategies are being developed to engage or mimic this pathway, including STING agonists, TLR agonists, and other innate immune activators. The molecular mechanisms that mediate the absence of the T cell-inflamed tumor microenvironment in patients are being elucidated using parallel genomics platforms and include tumorintrinsic oncogenic events, germline polymorphisms in immune regulatory genes, and the composition of the commensal microbiota. Each of these is giving rise to new therapeutic strategies to improve spontaneous immune infiltration and expand immunotherapy efficacy.
SY7 2
drugs. Especially, immuno-therapy with immune-checkpoint inhibitors including PD1 have brought dramatic changes in various cancer chemotherapy, not limited to treatment for melanoma. However, when it is monotherapy, the response rate is lower (ORR: less than 30%) and the duration until the effect onset is longer (more than 3 months) for Japanese patients than those for Caucasian patients. These problems result in further advancing of the disease or dropout from the therapy detected among 15% of the patients. Based on these circumstances in Japan, combination therapy (Nivolumab þ Ipilimumab) as a primary therapy has been introduced since August, 2018. This combination therapy has been given high expectations, as it has proven potent effect and early effect onset. However, it has strong and heavy adverse events and requires caution and prudent planning (i.e. biomarkers and selection of patients) for the proper application. In this symposium, I would like to present my own opinions by keywords including BRAF mutation positive, LDH, brain metastasis, multiple organ metastasis and primary therapy.
SY7 3
Immune checkpoint inhibitors: a perspective of established and potential combination therapy
Hidehito Horinouchi Department of Thoracic Oncology, National Cancer Center Hospital Monotherapy of immune checkpoint inhibitors has been dramatically changed the standard therapy of multiple types of cancer. The proportion of tumor expressing PDL1 is a clinically available biomarker for patient selection, however, there is still room for improvement. Combination of immune checkpoint inhibitors and other agents has been rigorously investigated to seek a better outcome. Other immune checkpoint inhibitors, cytotoxic agents, targeted therapy agents, and radiotherapy have been evaluated in lung cancer, kidney cancer, gastrointestinal tract cancer and other types of cancer. In this session, an overview of established and potential combination approach of immune checkpoint inhibitors and other agents will be provided.
Combination Immuno-therapy in Melanoma
Yoshio Kiyohara Dermatology Division, Shizuoka Cancer Center The prognosis of malignant melanoma in advanced stage used to be quite pessimistic, but there has been a paradigm shift going on in the lately, due to the newly-developed
C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz326.002/5582803 by University of Cambridge user on 06 November 2019
SY7 1
SYMPOSIUM 7 : FUTURE PROSPECTS OF IMMUNE CHECKPOINT INHIBITORS TUMOR AND HOST FACTORS REGULATING ANTI-TUMOR IMMUNITY AND IMMUNOTHERAPY EFFICACY
Thomas Gajewski University of Chicago, United States Characterization of the "T cell-inflamed" and "non-T cell-inflamed" tumor microenvironments has generated a framework for identifying immunotherapeutic targets and for understanding mechanisms of efficacy versus resistance. The T cell-inflamed phenotype includes expression of chemokines, T cell markers, and a type I IFN signature, whereas the non-T cell-inflamed phenotype lacks these factors and appears to display immune "exclusion". The mechanisms of immune escape are likely distinct in these two subsets, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3þ Tregs. Deep analysis of tumor antigen-specific T cells in the tumor microenvironment has identified additional mechanisms of immune dysfunction and new potential therapeutic targets, beyond PD-1. In contrast to the T cell-inflamed tumors, non-T cell-inflamed tumors are largely immunotherapy resistant with current approaches. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via Batf3-lineage DCs. New strategies are being developed to engage or mimic this pathway, including STING agonists, TLR agonists, and other innate immune activators. The molecular mechanisms that mediate the absence of the T cell-inflamed tumor microenvironment in patients are being elucidated using parallel genomics platforms and include tumorintrinsic oncogenic events, germline polymorphisms in immune regulatory genes, and the composition of the commensal microbiota. Each of these is giving rise to new therapeutic strategies to improve spontaneous immune infiltration and expand immunotherapy efficacy.
SY7 2
drugs. Especially, immuno-therapy with immune-checkpoint inhibitors including PD1 have brought dramatic changes in various cancer chemotherapy, not limited to treatment for melanoma. However, when it is monotherapy, the response rate is lower (ORR: less than 30%) and the duration until the effect onset is longer (more than 3 months) for Japanese patients than those for Caucasian patients. These problems result in further advancing of the disease or dropout from the therapy detected among 15% of the patients. Based on these circumstances in Japan, combination therapy (Nivolumab þ Ipilimumab) as a primary therapy has been introduced since August, 2018. This combination therapy has been given high expectations, as it has proven potent effect and early effect onset. However, it has strong and heavy adverse events and requires caution and prudent planning (i.e. biomarkers and selection of patients) for the proper application. In this symposium, I would like to present my own opinions by keywords including BRAF mutation positive, LDH, brain metastasis, multiple organ metastasis and primary therapy.
SY7 3
Immune checkpoint inhibitors: a perspective of established and potential combination therapy
Hidehito Horinouchi Department of Thoracic Oncology, National Cancer Center Hospital Monotherapy of immune checkpoint inhibitors has been dramatically changed the standard therapy of multiple types of cancer. The proportion of tumor expressing PDL1 is a clinically available biomarker for patient selection, however, there is still room for improvement. Combination of immune checkpoint inhibitors and other agents has been rigorously investigated to seek a better outcome. Other immune checkpoint inhibitors, cytotoxic agents, targeted therapy agents, and radiotherapy have been evaluated in lung cancer, kidney cancer, gastrointestinal tract cancer and other types of cancer. In this session, an overview of established and potential combination approach of immune checkpoint inhibitors and other agents will be provided.
Combination Immuno-therapy in Melanoma
Yoshio Kiyohara Dermatology Division, Shizuoka Cancer Center The prognosis of malignant melanoma in advanced stage used to be quite pessimistic, but there has been a paradigm shift going on in the lately, due to the newly-developed
C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz326.002/5582803 by University of Cambridge user on 06 November 2019
SY7 1