The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Guidelines and Consensus Statements Section Editor, Robert Ferris, MD, PhD, FACS.
“Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms” by Jean-Christophe Beltra et al
Reinvigorating exhausted T cells through blockade of the PD-1/PD-L1 axis has formed a critical foundation for cancer immunotherapy. However, the physiology and developmental biology that leads to the exhausted T cell phenotype (Tex) remains relatively poorly understood—especially in regards to the mechanisms underlying the profound heterogeneity seen in terminally differentiated exhausted T cells. Using a mouse model of chronic LCMV infection (that they confirmed in mouse B16 tumors and
tumor-infiltrating lymphocytes (TILs) from human melanomas), Jean-Christophe Beltra et al define four subpopulations of Tex: progenitor 1 (Ly108+CD69+), progenitor 2 (Ly108+CD69-), intermediate (Ly108-CD69-), and terminal (Ly108-CD69+). In the chronic infection model, PD-L1 blockade rebalanced the Tex population by promoting the expansion of the progenitor 2 and intermediate subsets. At steady state in the chronic infection model, the Ly108+ progenitor 2 population preferentially gained access to blood compared to the Ly108+ progenitor 1 subset. The intermediate subset also was found in the blood, whereas the CD69+ terminal Tex cells were strictly tissue resident. In terms of effector function, expression of Ly108 and CD69 was unaffected by peptide re-stimulation across all Tex subsets. Intermediate and terminal Tex cells mediated the most target killing in vitro. Proliferation ex vivo was restricted to the progenitor 1 subset (as well as slightly among the progenitor 2 group), though the overall capacity was far lower than that of memory T cells. Single cell RNA-seq revealed distinct clusters of differentially expressed genes for each Tex subset, consistent with acquisition of specific biological functions. Distinct changes in chromatin accessibility were also seen between the subsets, most notably transitions between the progenitor 2 and intermediate state as well as between the intermediate state and terminal state that coincided with altered availability of transcription factor binding sites. Conditional knockouts and enforced expression experiments demonstrated the centrality of TCF1/T-bet axis for the accumulation of the intermediate Tex subset. The findings are the first and most comprehensive characterization of transcriptional, the phenotypic, functional, epigenetic and anatomical differences between exhausted T cells, with potentially important implications for future checkpoint inhibition strategies.
“PPT1 inhibition enhances the antitumor activity of anti–PD-1 antibody in melanoma” by Gaurav Sharma et al
The autophagy pathway in tumor cells has been identified as a major resistance mechanism for chemotherapy and targeted therapy, however, single-agent autophagy inhibitors have returned mixed results in clinical trials regarding their effects on anti-cancer immunity. Guarav Sharma et al found that the lysosomal PPT1 inhibitor hydroxychloroquine combined with anti-PD-1 checkpoint blockade significantly impaired tumor growth in both the B16 and a BRAF mutant model of mouse melanoma. In co-culture experiments, knockdown of key autophagy genes in tumor cells (Ulk1, Pik3c3 (Vps34), and Atg7) led to significantly reduced interferon gamma production by T cells. By contrast, knockdown of PPT1 in B16 tumor cells di not impair T cell cytotoxicity. Notably, hydroxychloroquine (or a high-affinity derivative, DC661) treatment led to pronounced M2 to M1 phenotype switching, with significant
changes in inducible nitric oxide synthase (iNOS), arginase 1 (ARG1), and resistin like α/FIZZ1 (RETNLA/FIZZ1) as well as morphologic alterations. Furthermore, conditioned media from macrophages exposed to hydroxychloroquine or DC661 enhanced antigen-primed splenocyte-mediated killing of B16 tumor cells. In vivo, combination of anti-PD-1 and hydroxychloroquine treatment led to a three-fold increase in M1/M2 ratio while significantly reducing peripheral mononuclear myeloid-derived suppressor cells. Mechanistically, hydroxychloroquine and DC661 induced significant intracellular calcium release in M2 macrophages, leading to increased phosphorylation of p38, a result that was recapitulated by knockdown of PPT. Secretome analysis of M2 macrophages exposed to hydroxychloroquine showed enhanced expression of pathways regulated by cyclic GMP-AMP synthetase (cGAS) and stimulator of interferon genes (STING), culminating in interferon beta production. The findings reveal a new potential immunotherapeutic target in the autophagy pathway with already available inhibitory drugs, which could serve to augment antitumor immunity by multiple complementary pathways.
“Neoadjuvant and adjuvant pembrolizumab in resectable locally advanced, human papillomavirus unrelated head and neck cancer: a multicenter, phase II trial” by Ravindra Uppaluri et al
Pembrolizumab given alone or with chemotherapy has demonstrably improved survival and been approved by the US FDA for first-line treatment of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). Reasoning that checkpoint inhibitor therapy in the neodjuvant setting could possibly offer enhanced clinical benefits such as cancer downstaging, necessitating less intense adjuvant therapy, Ravinda Uppaluri and colleagues conducted a multicenter, phase II trial to determine if preoperative pembrolizumab for patients with resectable locally advanced, HPV-unrelated HNSCC would be safe and result in pathologic tumor responses (pTR). Among the 36 patients enrolled and treated, 50% had high-risk pathology. Neoadjuvant pembrolizumab administration was determined to be safe, with no serious adverse events observed through initiation of treatment and a 30-day window after surgery. Among the 12 patients who had high-risk disease and continued to receive pembrolizumab after surgery, one serious reversible immune-related adverse event occurred in the adjuvant setting: hypothyroidism, which was reversible. Pathological tumor response was defined as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes, with pTR-0 (less than 10%), pTR-1 (10% to 49%), and pTR-2 (50% or greater). After neoadjuvant pembrolizumab, pTR-2 was documented in specimens from eight patients (22%) and pTR-1 in eight additional patients (22%). The overall pTR rate of greater than 10% was 44% (16 of 36 patients). Proportions of pTR rates were balanced between high-and low/intermediate-risk groups. Immunological correlates of response by immunologic correlates of tumor response to neoadjuvant
pembrolizumab using immunohistochemistry, multiplex immunofluorescence and RNAseq on baseline samples included PD-L1 protein expression, CD8+ (but not CD4+) T cell infiltration, and expression of immune and inflammatory genes such as IFNG, CXCL9, CXCL10, CXCL11. Baseline tumor mutational burden and predicted neoantigen burden did not correlate with pTR. Next generation sequencing analyses on paired pre- and post-treatment samples (where available) hinted at possible clonal loss or expansion of de novo variants after treatment, but spatial heterogeneity and potential sampling bias complicates the interpretation of these results. Further studies of neoadjuvant pembrolizumab in patients with resectable HNSCC are warranted and deep biomarker analyses to clarify correlates of response should continue to be performed.
“Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: a phase II open-label randomized clinical trial” by Jonathan D Schoenfeld et al
Beyond being a high-risk malignant disease, oral cavity squamous cell carcinoma (OCSCC) provides a unique opportunity for clinical trials of immunotherapy in the adjuvant setting, due to the ability for visual monitoring throughout treatment. Jonathan D Schoenfeld and colleagues enrolled 29 patients with untreated OCSCC for randomization to either nivolumab monotherapy or nivolumab in combination with ipilimumab prior to surgery. No dose-limiting toxic effects were observed in the safety run-in for either cohort, and there was no statistically significant difference in the median time to onset of immune-related adverse events between the two study arms. The most serious adverse events occurred in the period following surgery or during standard-of-care adjuvant treatment, including grade 3 colitis and grade 3 pneumonitis in the nivolumab plus ipilimumab group and grade 4 new onset diabetes with accompanying ketoacidosis in the nivolumab monotherapy arm. Volumetric responses, responses by RECIST and downstaging were seen in both treatment arms and not significantly different between monotherapy and the dual regimen. Several cases of pathologic near complete response or complete responses were observed: one patient who was treated with nivolumab and three in the group receiving nivolumab with ipilimumab. In biomarker analyses, PD-L1 expression was not correlated with volumetric or pathologic response in the cohort. The degree of CD4+ T cell infiltration prior to treatment was linked to degree of pathologic response for the entire cohort, but this association was driven by the population receiving nivolumab and ipilimumab and not significant for the nivolumab-treated group alone. Fluorodeoxyglucose PET/CT scans were also performed after immunotherapy, and a decrease in avidity was seen in 15 patients overall, with patients achieving pathological tumor response of 50% or greater reduction in size. The findings demonstrate that nivolumab monotherapy as well as in combination with ipilimumab are well tolerated in the neoadjuvant setting for OCSCC, and point toward future biomarker analyses to identify predictors of clinical benefit.
“Reinvigorating NIH grant peer review” by Shane Crotty et al
National Institutes of Health (NIH) funding directly or indirectly supports the overwhelming majority of biomedical research in the United States, and peer review is the invisible engine that drives practically the entire mechanism of government supported inquiry by identifying what is truly worthwhile and potentially world-changing. Reacting to a recent concerning trend of NIH officials deemphasizing the importance of peer review in funding decisions, Shane Crotty and colleagues outline several suggestions for ways in which the experience for participants grant review study sections could be improved, making maximal use of the extremely limited resource of expert faculty time such that high-quality reviews may enable the identification and support of truly excellent science. The problem of recruiting reviewers is timely and applicable to all scientific disciplines, but especially for immuno-oncology, which is defined as a field by its interdisciplinarity, fast pace of advancement, and eager embrace of cutting-edge technologies. Leveraging their considerable experience acting as reviewers to suggest improvements that would reduce the activation energy required to evaluate a grant proposal. Areas for improvement include formatting adjustments to make the applications themselves less cumbersome to evaluate, reviewer incentives, logistical considerations, and, perhaps most importantly of all: coffee. The piece is a thought-provoking and provocative perspective that could, if even some of the suggestions were implemented, help bolster the prominence of the nation’s scientific enterprise.
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