Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma
Catherine S. GrassoJennifer TsoiMykola OnyshchenkoGabriel Abril-RodríguezPetra Ross‐MacdonaldMegan Wind‐RotoloAmeya S. ChamphekarEgmidio MedinaDavis Y. TorrejonDaniel Sanghoon ShinPhuong TranYeon Joo KimCristina Puig-SausKatie M. CampbellAgustin Vega-CrespoMichael J. QuistChristophe MartignierJason J. LukeJedd D. WolchokDouglas B. JohnsonBartosz ChmielowskiF. Stephen HodiShailender BhatiaWilliam SharfmanWalter J. UrbaCraig L. SlingluffAdi DiabJohn B.A.G. HaanenSalvador Martín‐AlgarraDrew M. PardollValsamo AnagnostouSuzanne L. TopalianVictor E. VelculescuDaniel E. SpeiserAnusha KalbasiAntoni Ribas
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Meeting abstracts Therapies targeting T cell immune checkpoints such as CTLA4 and PD1/PDL1 axis have shown considerable promise in the therapy of human cancer. Combination therapy with dual immune checkpoint blockade (ICB) was recently shown to be highly active in melanoma. While signaling via both
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Background: Increasing evidence supporting the role of immune checkpoint blockade in cancer management has been bolstered by recent reports demonstrating significant and durable clinical responses across multiple tumour types, including metastatic urothelial carcinoma (mUC).The majority of these results are achieved via blockade of the programmed death (PD) axis, which like CTLA-4 blockade permits T-cell activation and immune-mediated anti-tumour activity-essentially harnessing the patient's own immune system to mount an anti-neoplastic response.However, while clinical responses can be striking, our understanding of the biology of immune checkpoint blockade is only beginning to shed light on how to maximize and even improve patient outcomes with immune checkpoint blockade, especially in UC.Methods: We performed a literature review for immune checkpoint blockade with a focus on rationale for checkpoint therapy and outcomes in UC.We also highlight the advances made in other tumour types, with a focus on the recent 2015 meeting of the American Society for Clinical Oncology.Results: In heavily pre-treated UC, trials are suggesting objective response rates above 30%.These impressive results are seen across multiple different tumour types, especially those with high burden of DNA level mutations.Identification of prognostic biomarkers is currently under investigation, in order to improve patient selection.Interestingly, response to PD-1 directed therapy is seen even in patients with no evidence of PD-1 positivity on immunohistochemistry.This has led to the development of enhanced biomarkers including assessing DNA mutation rates and immune gene signatures, to improve patient selection.Conclusions: Immune checkpoint blockade is an exciting cancer treatment modality which is demonstrating impressive clinical results across multiple tumour types.For UC, anti-PD directed therapy represents a much needed treatment in the metastatic, post chemotherapy context.Potential for these agents to have clinical utility in non-metastatic UC is still to be assessed.
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Supplementary Figure from Circulating Immune Bioenergetic, Metabolic, and Genetic Signatures Predict Melanoma Patients' Response to Anti–PD-1 Immune Checkpoint Blockade
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It was widely accepted that programmed death-ligand 1 (PD-L1) positive, tumor mutational burden-high (TMB-H) or microsatellite instability-high (MSI-H) tumor are prone to have better treatment response to immune checkpoint blockade. The value of immune checkpoint blockade in PD-L1 negative gastric cancer patients has been questioned due to lower objective response rate (ORR).We report an unusual case of a PD-L1 negative, proficient mismatch repair (pMMR)/microsatellite stability (MSS), tumor mutational burden-low (TMB-L) gastric cancer patient who achieved good response to immune checkpoint blockade after failure of systematic treatment. Multiple lymph nodes and bone metastases are the main characteristics of this patient. The patient survived for more than 30 months after diagnosis.This case suggested that PD-L1 negative gastric cancer patient may also benefit from immune checkpoint blockade. In gastric cancer, patients with lymph node metastasis may be potential beneficiaries.
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<p>Supplemental Figure S6 describes that inhibition of NR4A2 or SQLE improves the therapeutic efficacy of immune checkpoint blockade.</p>
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