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 - April 2019

Dear JITC Readers,

In the April edition of the JITC Digest, let me call your attention to the following five articles of special significance. First, “Anti-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by anti-TGF-beta antibody to promote durable rejection and immunity in squamous cell carcinomas,” by E. Dodagatta-Marri et al. details the development and characterization of a novel panel of murine syngeneic SCC lines created to reflect the heterogeneity of human lung cancer and its responses to anti-PD-1 and anti-TGF-beta therapies. This study demonstrates that anti-PD-1 not only initiates a tumor rejection program, but can also induce a competing TGF-beta-driven immuno-regulatory program in SCCs, effects that were cooperatively blocked by combined PD-1 and TGF-beta inhibition.

Next, “Collagen density regulates the activity of tumor-infiltrating T cells,” by Dorota E. Kuczek et al. reports the use of 3D culture assays to investigate the role of collagen density as a direct regulator of anti-cancer T cell activity. Such results identify a new immune modulatory mechanism dampening T cell activity in the tumor microenvironment, which could constitute a novel therapeutic target for enhancing immunotherapy efficacy.

Furthermore, the article, “Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors,” by Mateusz Rytelewski et al. presents a novel imaging approach developed to elucidate the effect of oxygen tension on the efficacy of anti-tumor immune therapies. Data presented here analyzes the relationship between lymphocyte motility and oxygen distribution using ‘Fast’ Scanning Two-photon Phosphorescence Lifetime Imaging Microscopy (FaST-PLIM), a bi-modal imaging regimen that merges high-resolution oxygen imaging with fluorescence-based cellular tracking in in vivo models.

“Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy,” by Karin M. Knudson et al. describes for the first time the anti-tumor efficacy of subcutaneously administered IL-15 superagonist N-803 in combination with anti-PD-L1 checkpoint blockade in murine triple negative breast and colon carcinoma models which are non- and/or minimally responsive to either monotherapy. This study provides rationale for further assessment of the clinical potential of combining N-803 with blockade of the PD-1/PD-L1 axis.

Finally, Anne Monette et al.’s article, “Immune-enrichment of non-small cell lung cancer baseline biopsies for multiplex profiling define prognostic immune checkpoint combinations for patient stratification,” propose a novel, tumor heterogeneity reducing procedure to extract information from small tumor biopsies for companion diagnostic (CDx) tests for immunotherapy of lung cancer. Developed from immune-dense regions of core needle biopsies from a baseline NSCLC cohort, this new CDx is shown to profile infiltrating immune cell subsets, ICPs, proliferation, and effector T cell markers to better stratify patients for checkpoint blockade combinations using baseline biospecimens of all sizes.

With best regards,

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

To view the entire April 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. 

JITC Letter from the Editor - February 2019

Dear JITC Readers,

In the February edition of the JITC Digest, there are four articles of note of which I would like to highlight. First, the article “EnanDIM - a novel family of L-nucleotide-protected TLR9 agonists for cancer immunotherapy,” by Kerstin Kapp et al. reports the development of EnanDIM® molecules, a novel family of chemically defined TLR9 agonists with the ability to activate the innate and adaptive immune systems and elicit potent anti-tumor responses without generating off-target effects. The described immunological features of EnanDIM® molecules in this study suggest the potential for combination with other immunotherapeutic approaches and prompts the need for further preclinical and clinical development.

Next, the research article, “Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy,” by Aurelie Hanoteau et al. investigated clinically relevant in vivo models combining chemoradiotherapy (CRT) with two immunomodulatory drugs: cyclophosphamide (CTX) and L-n6-(1-iminoethyl)-lysine (L-NIL). Results demonstrated that alteration of the tumor immune microenvironment can render refractory tumors susceptible to CRT and suggests the potential for clinical translation of this approach.

Furthermore, the article, “Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial,” by Ulrich Keilholz et al. presents safety and efficacy data from previously treated patients with locally advanced or metastatic melanoma enrolled in the phase 1b, dose-expansion part of the JAVELIN Solid Tumor trial. Avelumab demonstrated durable responses and an acceptable safety profile, as well as encouraging efficacy for patients with PD-L1–positive tumors and those who had progressed after ipilimumab therapy.

Finally, Jana de Sostoa et al.’s article, “Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager,” details a novel strategy to minimize the antiviral immune response needed to target cancer calls and fibroblast activation protein-alpha (FAP). By inserting a bispecific T-cell Engager (FBiTE) targeting FAP into the oncolytic adenovirus, ICOVIR15K, Sostoa’s group developed an FBiTE-armed adenovirus (ICO15K-FBiTE) shown to enhance viral spread and overall anti-tumor efficacy without increasing clinical toxicity. Similar results with a similar FAP-BiTE were reported by an Oxford-based group using the oncolytic group B adenovirus enadenotucirev (Freedman JD et al. Cancer Res Dec 15, 2018).

Additionally, I welcome you all to enjoy a new feature through SITC Connect where JITC editors share a monthly reading list of publications of interest elsewhere in the field that add value to what readers can find in JITC. Check out the first edition of “JITC’s Reading List” and stay tuned for new content from each month’s featured editor.

With best regards,

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

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

The Tumor Glyco-Code and Why Immunologists Should Care About it

by Alexandra Cadena

In science, it’s so easy…tempting even to be sucked down the rabbit hole of a particular mechanism or biological pathway only to find that when you tease out one thread, multiple other avenues of research and discovery spring forth drawing you further and further into scientific specificity. Sometimes we get lost. Let’s say we get so caught up looking at a tree that we fail to see the forest.

I noticed this in a big way when I moved from researching in a lab that was solely dedicated to uncovering the effects of aberrant glycosylation in cancer to another lab solely focused on immunotherapy in combination with radiation. As I write this, I wonder, why do labs “solely” specialize in one arena?

Yes, I know the obvious answer is for funding purposes, but maybe the financial structure of how academic research is awarded in this country is hindering us rather than helping us. Are these “lab niches” in research stagnating us in that they prevent us from seeing the bigger picture? Maybe.

We have to specialize in one thing, and then we stay there, we don’t poke our head out to see what else is out there. One thing’s for sure, immunologists, or at least the ones I collaborate with, don’t give much thought to how glycosylation could be affecting the immune system in the fight against cancer. And I think considering glycosylation in the arena of immuno-oncology is one good step in the direction of looking at the bigger picture---or entire forest as it were.

Glycosylation and its by-product, the glycan, play a crucial role in many cellular processes. Aberrant glycan structures and mutations of the glycosylation pathway have been intricately linked with the development of cancer and more recently with cancer’s ability to escape the innate immune system. Glycosylation’s interaction with the immune system can promote tumor deviation through endogenous lectins, mutated, sialic acid domains and more….so why not move to combine some of our top of the line immune drugs with glycotransferase inhibitors?

This may even be the answer as to why some patients don’t respond to certain lines of immunotherapy treatment. In 2016, Li et al. presented findings in Nature Communications that found immunosuppression activity of PD-L1 was highly regulated by N-linked glycosylation. The Contessa lab group at Yale developed a small molecule inhibitor called NGI-1, which selectively inhibits N-linked glycosylation in only malignant cells. Fruitful collaboration? Possibly.

The tumor glyco-code may hold another secret for immunologists to unlock another avenue of tumor immune escape. There are some groups that are already starting to take note and develop glycan-based CAR T cells. In fact, the Carl June lab recently developed a Tn-MUC-specific CAR T cell, which has been effective in eliminating leukemia and pancreatic cancer in mice.

The advances in recombinant glycotransferase have given researchers the necessary tools to make antigens copy structures of tumor glyco-sites, which consequently enhances immunotherapy’s targeting of cancer. The advent of certain glycan therapeutics, such as glycan-based vaccines and glycotransferase inhibitors, have the potential to serve as powerful tools in combination with current immunotherapy drugs, but the important role they may play in the field of immuno-oncology can only be revealed if we continue to take a step back and see the larger picture and the vast forest that is the immune system, which expands well beyond the tumor microenvironment.

Dorsal Fins and Immune-Mediated Adverse Reactions

by Dr. Terence Rhodes

It is no small secret that I have galeophobia. It is a moderate case. It doesn’t keep me from the beach.  My top choice for vacation is the beach. Sun, slumber, sand, and the sound of the crashing waves is a recipe for relaxation. Venturing into the ocean water, however, is a concoction for anxiety. What lurks beneath the waves? 

The phobia of sharks likely comes from my over-consumption of news and media. From “Jaws” to the latest “Sharknado (Sharknado 5: Global Swarming),” sharks have terrorized movie characters and moviegoers alike for decades.