JITC Letter from the Editor - June 2019

Dear JITC Readers,

In the June edition of the JITC Digest, I would like to draw special attention to the following articles. First, “Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors” by Sonia Domingos-Pereira et al. investigates the effects of systemic administration of a chemotherapy doublet in combination with HPV16-E7 synthetic long peptide (E7LP) vaccination, followed by intravaginal immunostimulation in the genital orthotopic TC-1 mouse model. Results from this study suggest that combining novel vaccine formulations with local immunostimulation and standard-of-care chemotherapy have the potential to benefit patients with HPV-associated cancer.

Next, the research article “Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node,” by Kim M. van Pul et al. describes the immune status of breast draining lymph nodes (LN) in a quantitative and functional manner using multi-parameter flow cytometry and ex-vivo cultures, and compares it with that of breast-draining axillary LN from healthy donors. This study provides new insights into the mechanisms underlying loco-regional immune suppression in breast cancer and how this relates to clinical parameters and suggests that LN-resident-conventional dendritic cells are potential therapeutic targets.

Furthermore, the article, “Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies,” by Victoria M. Kim et al. shows for the first time, that a Listeria vaccine-based immunotherapy was able to induce a tumor antigen-specific T cell response within the tumor microenvironment of a “cold” tumor such as PDAC and further sensitizes the tumor to checkpoint inhibitor therapy. This combination immunotherapy led to objective tumor responses and survival benefit in mice with spontaneously developed PDAC tumors, supporting Lm-ANXA2 as a therapeutic agent in combination with anti-PD-1 antibody for PDAC treatment.

“Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study,” by Douglas B. Johnson et al. leverages Vigibase, the World Health Organization pharmacovigilance database, to further define neurologic toxicities in the largest characterization of neurologic immune-related adverse events (irAEs) associated with ICIs. Results of this analysis pinpointed several categories of neurologic toxicities strongly associated with CNS inflammation or peripheral neuromuscular autoimmune disorders of which clinicians should be aware of in administering checkpoint blockade.

Finally, Hyun Gul Yang et al.’s article, “Discovery of a novel natural killer cell line with distinct immunostimulatory and proliferative potential as an alternative platform for cancer immunotherapy,” presents a novel NK cell line, NK101, from a patient with extra-nodal NK/T cell lymphoma and an assessment of its phenotypic, genomic and functional characteristics, with results suggestive of its therapeutic application as a CAR T-alternative anti-cancer cellular platform with improved efficacy and superior scalability.

With best regards,

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

To view the entire June 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. 

Viruses come to help T cells in fighting tumors

by Dr. Saman Maleki

Oncolytic viruses are emerging as promising therapeutic agents in the fight against cancer.

Last year, the U.S. FDA approved Talimogene laherparepvec (T-Vec)–a genetically modified Herpes Simplex Virus Type 1 replicating in tumor cells and producing GM-CSF–for the local of treatment of patients with unresectable metastatic melanoma^1. Tumor cells often have a defective intrinsic antiviral response because of their immune evasive and neoplastic characteristics, which makes them ideal hosts for viral infections^2. Furthermore, viruses preferential targeted replication in cancer cells has shown acceptable safety profile in clinical trials^2.