Dear JITC Readers,In the July edition of the JITC Digest, I would like to draw attention to the following articles. First, “Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma” by Robert H. I. Andtbacka et al. reports the final analysis of OS, objective response and complete responders in the OPTiM trial performed 3 years after the last patient was randomized. Compared to GM-CSF, T-VEC resulted in durable CR rates associated with prolonged survival, most notably in patients with early metastatic melanoma (stage IIIB–IVM1a).
Next, the research article entitled “DNA damage repair gene mutations and their association with tumor immune regulatory gene expression in muscle invasive bladder cancer subtypes,” by Thiago Vidotto et al. investigated the pre-treatment immune landscape for patients with muscle invasive urothelial cancer (MIUC) using the Cibersort tools. Through correlation of immune regulatory gene expression profiles from the TCGA, this study tests the hypothesis that pre-treatment immune contexture and subsequent response of MIUC is dictated by cancer cell intrinsic events such as DDR deficiency. Results suggest a potential co-activation of multiple compensatory immune checkpoint pathways in pre-treatment MIUC, and warrant further development of combined biomarker and immunomodulatory treatment approaches in UC.
Furthermore, the article, “PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes,” by Jesús Ogando et al. analyzed gene expression profiles of human CD8+ T cells in conditions that mimic simultaneous engagement of PD-1 and the TCR/CD3 complex. This study points to mitochondria as the main targets of PD-1 inhibitory activity and shows that PD-1 engagement triggers a specific, time-dependent genetic program different from that in resting cells, suggesting that in addition to blocking TCR-mediated signals, PD-1 can target specific signaling pathways that dysregulate T cell function, including glycolysis and oxidative phosphorylation.
“Tumor-associated macrophage expression of interferon regulatory Factor-8 (IRF8) is a predictor of progression and patient survival in renal cell carcinoma,” by Jason B. Muhitch et al. investigated whether levels of IRF8, a protein recently identified in nephrectomy and metastatic tissues from ccRCC patients as a regulator of myeloid-derived suppressor cells (MDSCs) and macrophage responses to pathogens, correlated with disease progression. This study evaluated IRF8 expression by TAMs and provides the first evidence that protein expression of this transcription factor is decreased in advanced stage patient specimens and may be used to predict long-term survival in a subset of ccRCC patients.
Finally, Marit M. Melssen et al.’s study, “A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund’s adjuvant in melanoma patients,” tested whether vaccination with 12 short melanoma peptides in combination with TLR agonists (polyICLC or LPS) with or without IFA was both safe and immunogenic in melanoma patients. In contrast to the study hypothesis, peptide-specific CD8 T cell responses were more durable and of greater magnitude when IFA was included as an adjuvant, regardless of whether it was combined with polyICLC or LPS.
With best regards,
Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer
To view the entire July 2019 JITC Digest, please click here.
