JITC Letter from the Editor - November 2019

Dear JITC Readers,

You are receiving this email in the weeks after SITC’s 2019 Annual Meeting and Pre-Conference Programs. This year’s meeting was a smashing success, truly highlighting the broad spectrum of basic science and clinical and translational research in immunotherapy. It is an exciting time for the field, and we are looking forward to possibly seeing some of the data presented at the meeting in upcoming issues of JITC.

Additionally, I am delighted to announce that Dr. Jason Luke, of the University of Pittsburgh Medical Center Hillman Cancer Center, has accepted the role of JITC’s social media editor! Dr. Luke will be managing the journal’s recently launched twitter handle. Be sure to take a moment to follow @JITCancer.

This month’s JITC digest exemplifies the interdisciplinary nature of immunotherapy research, with everything from basic insight into T cell metabolism and immunology to clinical trial results and next-generation sequencing.

“TLR9 acts as a sensor for tumor-released DNA to modulate anti-tumor immunity after chemotherapy” by Tae Hung and colleagues reveals new insight into how platinum-based chemotherapy can act as an immune adjuvant through innate immune danger-sensing pathways.

A review by Bridget P. Keenan et al., “Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response,” describes the delicate balance between protective immunity in the liver and pathological inflammation that may lead to cirrhosis, fibrosis and cancer.

Beatris Mastelic-Gavillet et al. elucidate how adenosine within the tumor microenvironment contributes to disease progression by metabolic suppression of effector T cells. The paper, “Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells,” outlines potential biomarkers to monitor future immunotherapies targeting adenosine signaling.

In “Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma,” Indu Ramachandran et al. provide the first evidence for affinity-enhanced receptor engineered SPEAR T cells infiltrating solid tumors—a promising result for the treatment of synovial sarcoma and other malignancies that fail to respond to immune checkpoint blockade.

Finally, Zijun Y. Xu-Monette and colleagues undertake impressive and comprehensive ultra-deep sequencing to identify differential links between somatic hypermutation in immunoglobulin heavy and light chains and clinical outcomes in diffuse large B cell lymphomas in, “Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.”

I hope you enjoy this issue!

With best regards,

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

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

JITC Letter from the Editor - October 2019

Dear JITC Readers,

I am pleased to share news of the launching of JITC’s very own Twitter handle (@JITCancer). Managed by JITC’s very own editors, this new platform will provide followers with access to JITC’s latest publications as well as cutting-edge news from throughout the fields of tumor immunology and cancer immunotherapy. Furthermore, it will give authors, readers, and editors a place to connect more directly on a global level.

If you use Twitter, please take a moment to follow @JITCancer and explore its social content. The October edition of the JITC digest also contains several highlighted articles that may be of interest for you to share with your followers. In particular, these highlighted articles show how insight into the interplay between malignant cells and the immune system can unlock new therapeutic strategies and diagnostic tools.

Two papers reveal new insight into which patients may benefit from checkpoint inhibition. The first, “Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma” by Swati Gupta et al., develops a profile based on mRNA expression signatures of four genes (CD274 (PD-L1), PDCDILG2 (PD-L2), CD8A, and IRF1) that correlates with clinical outcomes in melanoma patients treated with anti-PD-1 immunotherapy. With further development, the approach they describe could offer a rapid-turnaround companion diagnostic, without standardization and threshold issues inherent in immunohistochemistry-based diagnostics.
The second article addresses the ongoing question of how T cell responses determine outcomes of checkpoint inhibition. Fehlings et al. shine some light on this issue by identifying a distinctive population of neoantigen-specific CD8+ effector-like T cells in PBMCs from patients with non-small cell lung cancer who responded to anti-PD-L1 treatment. Their findings are described in, “Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment.”

T cell engineering has emerged as an exciting new clinical frontier, with the marked success of chimeric antigen receptor (CAR)-based therapies. In, “A TIGIT-based chimeric co-stimulatory switch receptor improves T cell anti-tumor function,” Hoogi et al. deploy a novel T cell engineering strategy, generating a chimeric costimulatory switch receptor (CSR) that circumvents inhibitory signaling in the cancer milieu by fusing the extracellular ligand-binding domain of the co-inhibitory receptor TIGIT to the intracellular stimulatory domain of CD28. T cells co-transduced with both an antigen receptor and the CSR displayed enhanced cytokine production in vitro and prolonged survival in xenograft models of established melanoma.

The final paper highlighted in this month’s digest describes encouraging results from a phase 1 trial of a humanized anti-IL-8 monoclonal antibody in 15 patients with incurable metastatic or unresectable, locally advanced solid tumors. Bilusic et al. demonstrate that IL-8 blockade is safe and well-tolerated in, “Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors.” What’s more, 11 out of 15 patients achieved stable disease, an encouraging result for ongoing studies investigating IL-8 blockade in combination with checkpoint inhibition.

With best regards,

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

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

JITC Letter from the Editor - September 2019

Dear JITC Readers,

There are several recent articles I would like to highlight in this September issue of the JITC digest, pointing to the progress we’ve been making toward understanding the immune system and cancer.

First, “PD-1 silencing impairs the anti-tumor function of chimeric antigen receptor modified T cells by inhibiting proliferation activity” by Jianshu Wang et al demonstrates yet another function of PD-1 in T cells. In this case, knock-down of PD-1 does not lead to increased anti-tumor activity; rather, silencing of PD-1 in CAR T cells inhibits their proliferation capability and differentiation, and impairs their anti-tumor effects.

“Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1” by Suzanne Thomas et al outlines the potential of a novel HSV-1-based oncolytic platform, whereby the engineered virus is armed with various modifications to increase its therapeutic effects, essentially allowing effective combination therapy through a single administered agent.

In the article, “Concurrent therapy with immune checkpoint inhibitors and TNF-alpha blockade in patients with gastrointestinal immune-related adverse events”, Yousef R. Badran and co-authors provide insight into management of one of the most common immune-related adverse events, enterocolitis. They describe five patients treated concurrently with checkpoint inhibitors and infliximab, all of whom had symptom resolution and disease control, providing physicians an example for management or severe cases of this common side effect. While the efficacy of this combination to control immune related enterocolitis awaits formal confirmation in controlled clinical trials, the results are indeed in line with recent observations in pre-clinical studies (Perez-Ruiz et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy, Nature 2019).

Daruka Mahadevan et al describe a novel immune checkpoint inhibitor in “Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200”. In this first-in-human study, the authors observed encouraging efficacy through blockade of CD200 in hematologic malignancies, recommending further dosing optimization for future investigations.

Finally, “Characterization of a whole blood assay for quantifying myeloid-derived suppressor cells” by Minjun C. Apodaca et al addresses a pressing issue with a promising biomarker: quantification of circulating myeloid-derived suppressor cells. They identify a common pathway to their quantification using flow cytometry, and also point out a few pre-analytical variables that have significant impact on MDSC levels as well.

With best regards,

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

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

JITC Letter from the Editor - July 2019

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. 

JITC Letter from the Editor - May 2019

Dear JITC Readers,

In the May edition of the JITC Digest, I would like to call your attention to the following five articles of special interest. First, “Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity” by Elena E. Tchekneva et al. investigates the specific roles of Notch ligands in modulating T cell responses through genetic and pharmacological approaches in mouse models of lung and pancreatic tumors and cardiac allograft rejection. This study emphasizes the importance of specific expression of Notch ligands on dendritic cells by revealing their distinct roles in the regulation of T cell immunity, and suggests opportunities for modulating immune outcomes using engineered Notch ligand constructs.

Next, “Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen,” by Stefanie K. Wculek et al. discusses the potential of using natural conventional type 1 DCs (cDC1s) as a syngeneic vaccine in cancer therapy and in a proof-of-principle study, demonstrates the feasibility and efficacy of a personalized anti-cancer treatment based on cross-presenting cDC1-based vaccination that does not require identification of tumor neoantigens. Such results provide valuable pre-clinical data regarding the efficacy of therapeutic cDC1-based anti-cancer vaccination for the development of next-generation DC vaccines.

Furthermore, the article, “CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids,” by Reyes Gonzalez-Exposito et al. describes the benefits of using 3D in vitro patient derived organoid (PDO) models in place of patient cells lines to better represent the biological characteristics of patient tumors. The authors assess carcinoembryonic antigen (CEA) expression heterogeneity as a common finding in colorectal cancer PDOs from therapy resistant metastatic CRCs and the possible mechanisms by which resistance to cibisatamab immunotherapy may occur.

“Exploring the emerging role of the microbiome in cancer immunotherapy,” by Jessica Fessler et al. examines recent research on the bacterial component of the microbiota, the connection between certain bacteria and the process of carcinogenesis, as well as implications for how the microbiota may be modulating the efficacy and toxicity of cancer immunotherapy. Importantly, this review suggests future clinical implications involving exploitation of the host-microbiome interdependency for delivery of more potent therapy.

Finally, Marjolaine Debant et al.’s article, “STIM1 at the plasma membrane as a new target in progressive chronic lymphocytic leukemia,” extensively analyzes calcium entry in CLL cells, revealing that in patients with progressive disease, calcium signaling deregulation may be due to a constitutive and B cell receptor (BCR)-independent calcium entry pathway involving membrane-associated STIM1. This study warrants further evaluation of a mAb targeting STIM1PM in cancer therapy alone or in combination.

With best regards,

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

To view the entire May 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. 

JITC Letter from the Editor - January 2019

Dear JITC Readers,

In the January edition of the JITC Digest, there are four noteworthy articles of which I would like to draw special attention. First, the article “Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication,” by Gijs G. Zom et al. reports novel murine data demonstrating the enhanced immunological potency of the novel TLR2-ligand, Amplivant (AV), as an adjuvant in cancer immunotherapy. Such results lay the foundation for further clinical testing of AV-synthetic long peptide (SLP) conjugates.

Next, the research article, “1-Pyrroline-5-carboxylate released by prostate Cancer cell inhibit T cell proliferation and function by targeting SHP1/cytochrome c oxidoreductase/ROS Axis,” by Yutao Yan et al. establishes a crucial immunosuppressive mechanism utilized in prostate cancer by which metabolites released by prostate cancer cells directly impair T cell immunity and anti-tumor functionality.

Furthermore, the article, “Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy,” by George Fromm et al. details the development and characterization of Agonist Redirected Checkpoint™ (ARC), a dual-sided Fc fusion protein platform for the linking of specific checkpoint and costimulatory pathways. Fromm’s group specifically reports on the anti-tumor response and potential therapeutic activity of the prototype ARC molecule, PD1-Fc-OX40L, for both human and mouse.

Finally, Larissa S. Carnevalli et al.’s article, “PI3K-alpha/delta inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity,” examines the immune response elicited by AZD8835, a dual PI3K-alpha/delta inhibitor, through preclinical syngeneic tumor models and determines how differential dosing of the inhibitor affects anti-tumor immunity through interactions with the tumor immune microenvironment.

With best regards,

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

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

Cancer Immunotherapy: Simplified…

by Kushal Prajapati

In the field of cancer research, Cancer Immunotherapy, Immuno-Oncology or I-O have been buzzwords for quite a few years now. For those who are not life science professionals but actively follow the developments in the field, these may be some popular terms come across on TV, newspapers or magazines. Yet for many, including some scientists not very familiar with immunology, the understanding of how immunotherapy could treat cancer remains either elusive or a mystery. In this blog, I will try to simplify some key principles of Immuno-Oncology for anyone who has always wanted to learn more about this revolutionary field.

Our body is nature’s highly sophisticated creation equipped with a very efficient defense called the immune system. This immune system is made up of different kinds of cells, each specialized in carrying out certain tasks. One of the cell types, known as killer T cells, can identify the foreign cells/invaders in the body and kill them (yes, literally). You could think of them as the ‘soldiers’ of your body who know how to find intruders and neutralize them. In Immuno-Oncology, scientists use these T cells to recognize and kill cancer cells. But wait…cancer cells are your own cells, not foreigners, right? Why would T cells kill your own cells?! The answer to this lies in the fundamentals of how the T cells identify their targets.

Every healthy cell in our body needs to present a normal pattern of immunological signals, called ‘antigens’, to be accepted as ‘self’ or ‘body’s own’ by the immune system. However, when a cell incurs numerous genetic mutations and/or the biological processes within it go haywire, this pattern of antigen presentation is changed enough to label the cell as ‘foreign’ in the eyes of the immune system. This is often the case for cancer cells. T cells would then identify the abnormal antigens on cancer cells using their receptor- called T cell receptor - and get rid of these cells. But if it was this simple, then no one would ever get cancer as the T cells would keep killing the cancer cells as and when they arise. Hence, there is something that’s certainly not very efficient about this process. While we don’t completely understand the underlying reasons yet, the scientists have been able to turn the tables on cancer by strengthening the T cells’ anti-tumor activity in two major ways in the clinic so far.

The first one is chimeric antigen receptor (CAR) T cell therapy which enables T cells to recognize the cancer cells that are otherwise undetectable. As we talked about antigen presentation in previous paragraph, it is worth knowing that many cancer antigens exist in forms that are not recognizable by the T cell receptors. Consequently, these antigens always go undetected by the T cells. CAR was designed to overcome this limitation. It combines a part of the natural T cell receptor with a part of an antibody that can recognize a desired antigen (the one that’s unrecognizable by T cell receptor). Just like giving a new tool to a solider to spot a hidden enemy! With this technology, scientists can identify new cancer antigens invisible to the immune system, design CARs against them, and put them into our T cells to empower them to accurately kill those cancer cells.

The second approach, called the ‘check-point’ blockade, basically stops the T cells from being stopped by cancer cells. In general, T cells in our body are always on the call of duty, looking out for threats and dealing with them. In this scenario, our body has natural mechanisms in place to control the T cells from over-reacting and potentially hurting the healthy cells. One such mechanism is ‘check-point’ signaling, wherein the T cells that are over-worked show significant presence of check-point receptors like PD-1 and CTLA-4 which serve as ‘brakes’ on them. It’s when these receptors (brakes) are ‘engaged’ by the molecules called check-point ligands, the T cells slow-down their function or stop completely. This very mechanism is exploited by cancer cells to escape the immune system. They increase the engagement of the brakes (PD1, CTLA-4) on T cells by simply increasing the amounts of check-point ligands- resulting in attenuation of T cell function. To tackle this problem, researchers developed antibodies which block the interaction between check-point receptors and their ligands. This allows the T cells to continue killing cancer cells without stopping! So far, the check-point blockades of PD-1 and CTLA-4 signaling have shown resounding success in treating many cancers in the clinic.

So, do we finally have the magic bullet against cancer? Not quite yet. The clinical success of immunotherapy has been exciting; however, studies show that most patients do not respond to it if they have more aggressive, solid tumors. However, the good news is that years of research work has revealed to us biological reasons (e.g. various ways the cancer fights back against immune system) behind failure of immunotherapies in such cases. As the new treatments developed based on this knowledge make their way into the clinical trials, exciting times are waiting ahead for cancer immunotherapy! 

[Disclosure: This blog is intended to educate general public and non-experts about the basic concepts of cancer immunology and clinically available immunotherapies. The author does not intend to undermine the efforts behind other cancer immunotherapy approaches that are currently under clinical investigation]

Q&A with SITC Vice Presidential Candidate Patrick Hwu, MD

In celebration of Cancer Immunotherapy Month™, we’ve asked SITC leaders to participate in a Q&A series for The Sentinel. We’ve asked them to briefly share why they entered the field, advice they’d share with early career scientists considering a career in cancer immunotherapy and more.

Please see below the Q&A from Patrick Hwu, MD, of University of Texas MD Anderson Cancer Center. Dr. Hwu is a 2018 candidate for SITC Vice President. Learn more about his candidacy here. Voting for the 2018 SITC Election takes place June 14–28, 2018.

1. What initially excited or intrigued you about the cancer immunotherapy field to choose this as your career focus?

When we get a viral infection, we can get very sick, but almost always fully recover. This powerful ability of the immune system to naturally cure viral illnesses has always intrigued me and encouraged me that applying this system against cancer could be impactful. In addition, the non-specificity and toxicity of current cancer therapies, such as chemotherapies, have always seemed unpalatable to me.  T-cells have the ability to distinguish normal peptides from mutated cancer-associated peptides that differ in merely one amino acid. This ability can enable anti-cancer therapies that have high efficacy and low toxicity. Even though immunotherapies in the early days were quite toxic, recent advances have allowed us to get closer to this dream of efficacious therapies without much toxicity. I routinely now have patients who travel to Europe and other distant places on vacation in between their outpatient treatments of immunotherapy. 

2. What advice would you share to an early career scientist contemplating a career in cancer immunotherapy?

Go for it!!  This is an exciting field.  I somewhat envy young investigators entering the field now. We know so much more than we knew when I was starting out, such as many of the immunoregulatory mechanisms of the body, and now have such great techniques like CyTOF and single cell RNA-seq to rapidly answer questions. Be curious, focused, and resilient. Many young investigators are intimidated by challenges with obtaining research funding. But there are in fact many more sources of funding now than traditionally in academia in years past. There is so much potential for us to make a great impact in cancer care, and we need as many talented young minds working on this as possible. Finally, don’t let anyone tell you something is impossible. In the early days, there were only a few of us who believed in immunotherapy and it is gratifying to see how many “converts” we have now.

3. What are three of the biggest hurdles facing researchers in the field, and how do you think they can be solved?

1. Moving immunotherapy responses beyond the common “immunogenic” tumor types.  In my opinion, this is largely due to the lack of sufficient CD8+ T-cells recognizing these cancers, i.e., lack of T-cell priming. This can potentially be solved using cancer vaccines, T-cell therapy and intratumoral immunomodulation, which are all very exciting and promising approaches.
2. Insufficient numbers of young investigators entering the field. Because of the challenges of funding, as well as the lack of enthusiasm for immunotherapy for many years in the past, there is a large deficit of talented, trained immunotherapy investigators. While this is starting to correct itself naturally, we need to move forward with urgency to train additional basic, translational and clinical investigators so we can fulfill the promise of immunotherapy to help the many cancer patients in need of better treatments.
3. Scalability with current approaches. Many of the most exciting current approaches towards immunotherapy, such as T-cell therapy and personalized vaccines, may have challenges with scaling treatments to the population in need in an affordable fashion.  There are many financial pressures on our current health care system, and biologists, engineers, politicians, and the business community must work together to bring these exciting therapies to the many people who need them.

4. What area of research has you most excited for the future of the field, and why?

I am most excited about the many ways we can prime the immune system to induce larger numbers of T-cells able to recognize cancers, many of which are considered “non-immunogenic.” While much of the field has focused on the release of immune checkpoint blockade, this will be ineffective if there is insufficient numbers of specific T-cells recognizing the cancer to begin with. Cancer vaccines, T-cell therapy, and intratumoral immunomodulation (for example, with TLR or STING agonists) are all very exciting areas with much promise. Combining these approaches in a rational way with other immunotherapies and targeted therapies also has much potential.  

In to I-O: First Contact

by Dr. Nils Rudqvist

My name is Nils Rudqvist and I have a confession to make: a few years ago, fresh out of grad school, I barely knew what a T cell was. I knew even less about dendritic cells, and don’t get me started on macrophages. I mean, I knew of them, but my understanding was very limited. I understood that the immune system worked hard to keep me safe and healthy, but also that it could malfunction - evident from my friend’s constant joint pain.

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.