JITC Letter from the Editor - August 2019

Dear JITC Readers,

In the August edition of the JITC Digest, I would like to highlight the following articles. First, “The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC),” by Ezra E.W. Cohen et al. details the first new FDA approvals for patients with squamous cell carcinoma of the head and neck (HNSCC) since 2006, including the most recent 2019 approval of pembrolizumab as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC in combination with chemotherapy for all patients or as monotherapy for patients with HNSCC whose tumors express PD-L1. These consensus guidelines serve as a foundation to assist clinicians’ understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit.

Furthermore, the article, “T cells expressing NKG2D chimeric antigen receptors efficiently eliminate glioblastoma and cancer stem cells” by Dong Yang et al. confirms the high expression of NKG2DLs in human glioblastoma cell lines, CSCs, and tumor samples and provides evidence that NKG2D CAR T cells effectively target glioblastoma cells and CSCs in an NKG2D-dependent manner, thus reporting on an encouraging therapeutic approach for glioblastoma patients.

Next, the research article entitled “Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2–IL-6 cascade,” by Yong-Qiang Chen et al. reveals novel cellular and molecular mechanisms of tumor-derived extracellular vesicles in regulating CD4+ effector T cell function and pinpoints tumor cell-released autophagosomes (TRAPs) as a therapeutic target for cancer immunotherapy, specifically reporting HSP90-alpha on the surface of TRAPs as a novel target.

“Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments,” by Shreya Raghavan et al. details the hanging drop spheroid model developed to investigate pro-tumoral macrophage activation in response to CSCs and the role of WNT pathways in CSC-macrophage interactions. Such insight could provide new targets for reducing CSC-burden in ovarian cancer.

“HERA-GITRL activates T cells and promotes anti-tumor efficacy independent of Fc-gamma-R-binding functionality,” by David M. Richards et al. describes the development of a novel agonistic HERA molecule targeting GITR for which the underlying HERA-GITRL structure overcomes significant limitations of bivalent antibody-based approaches by mimicking the natural trimeric ligand, and thus inducing optimal trimeric assembly of the GITR receptors.

Finally, the clinical study, “First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors,” by Kohei Shitara et al. reports on single agent IT1208, a humanized anti-CD4 immunoglobulin G1 mAb, which is shown to successfully deplete CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, warranting further investigations, possibly in combination with immune checkpoint inhibitors.

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire August 2019 JITC Digest, please click here. 

JITC Letter from the Editor - March 2019

Dear JITC Readers,

In the March edition of the JITC Digest, there are five important articles of which I would like to draw attention. First, the article “HDAC6 selective inhibition of melanoma patient T-cells augments anti-tumor characteristics,” by Andressa S. Laino et al. details the development of two HDAC6-selective inhibitors, ACY-1215 and ACY-241 as modulators of human T cell properties. Through ex vivo studies and at concentrations achievable in human patients, the reported HDAC6 inhibitors did considerably enhance melanoma patient T cell functions suggesting potential therapeutic efficacy.

Next, the research article, “Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1,” by Kellie N. Smith et al. reports two cases of patients with biomarker-negative tumors (low mutational burden, negative for PD-L1, MMR proficient), each of which maintained a T cell response to a hotspot oncogenic mutation years after treatment initiation and both of whom derived durable clinical benefit from PD-1 blockade. Such results demonstrate that driver mutations may elicit efficient and durable anti-tumor immune responses and augment clinical response to immunotherapy.

Furthermore, the article, “Cancer-cell-secreted CXCL11 promoted CD8+ T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC,” by Qun Gao et al. presents novel data demonstrating the ability of docetaxel to upregulate CXCL11 in the tumor microenvironment through the release of HMGB1, subsequently driving the recruitment of CD8+ T cells and eliciting an improved immune response. This data supports the further development of clinical studies to measure anti-tumor immune response after docetaxel treatment in cancer patients.

“The IL-1/IL-1 receptor axis and tumor cell released inflammasome adaptor ASC are key regulators of TSLP secretion by cancer associated fibroblasts in pancreatic cancer,” by Emanuela Brunetto et al. identified tumor-derived IL-1-alpha and IL-1-beta as key cytokines in driving thymic stromal lymphopoietin (TLSP) secretion by cancer associated fibroblasts and tumor-released ASC. Results also demonstrate that treatment with an IL-1R antagonist significantly reduces TSLP expression in in vivo tumor models, providing support to the further assessment of therapies which aim to interfere with such pathways.

Finally, Cynthia Perez et al.’s article, “NKG2D signaling certifies effector CD8 T cells for memory formation,” shows that signaling through NKG2D in primary effector CD8 T cells is required for their differentiation into functional memory cells. As a better understanding of how long-term memory cells are formed from the initial effector pool of CD8 T cells remains an essential objective in immunology, this process of “memory certification” provides important clues to the development of improved vaccines and adoptive cellular therapies.

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire March 2019 JITC Digest, please click here.