Letter from the Editor- April

Dear JITC Readers,

It is a pleasure to welcome you to this month’s JITC digest. The original research articles highlighted in this edition are fantastic examples of mechanistic insight interwoven with new strategies for intervention and vice versa—the seamless reverse translational cycle that is central to the immunotherapy field.

 

Novel targets for immunotherapy are characterized by Aiqin Gao and colleagues, who show that blocking ILT4 relieves T cell immunosenescence via ERK-dependent metabolic perturbations, as well as François Anna et al, who take aim at HLA-G with the first chimeric antigen receptor (CAR) T cells against the dual function tumor-specific antigen and immune checkpoint.

 

Esther Redin and colleagues demonstrate that inhibition of the SRC-family kinase YES1 with the approved leukemia drug dasatinib decreases CD4+ Treg conversion and enhances the efficacy of PD-1 blockade in non-small cell lung cancer.

 

Another strategy to augment the anti-tumor effects of PD-1 inhibition is identified by Yoke Seng Lee et al, who establish a link between conventional type 1 dendritic cell counts and responses to immunotherapy in patients with melanoma as well as in a novel humanized mouse model.

Finally, Gino M Dettorre and colleagues validate a readily available index of hyperinflammation incorporating lymphopenia and hypoalbuminemia that predicts outcomes of SARS-CoV-2 infection in patients with cancer—research that hints at interventions to prevent severe disease and nicely complements recently published articles in JITC’s ongoing COVID-19 and Cancer Immunotherapy Review Series.

 

Best regards,

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

To view the entire April 2021 JITC Digest, please click here. 

JITC Review Series: Immune Checkpoints Beyond PD-1

Checkpoint blockade—therapies that disrupt the interaction between co-inhibitory receptors on T cells and their cognate ligands thereby blunting activation and proliferation despite antigen engagement—is a testament to the power of translational research. What began as a curiosity-driven inquiry into the mechanisms of immune tolerance has blossomed into a fourth pillar of cancer treatment, complementing the traditional triumvirate of chemotherapy, surgery, and radiation to provide remarkable benefits to thousands of patients.   

The discovery of immune checkpoints spurred a renaissance in immuno-oncology, with parallel efforts directed at translating known mechanisms of T cell inhibition into clinically available therapies as well as at the identification of additional targets.

In the past year alone, more than one dozen new approvals were granted in the US for immunotherapies targeting the PD-1/PD-L1 axis. With more than 3,000 active clinical trials evaluating these regimens, not only for advanced or metastatic disease but also in the adjuvant or neoadjuvant settings, the pace of approvals for checkpoint inhibitors is not looking to slow down any time soon.

Despite this unprecedented advancement, a large subset of cancer patients do not respond to PD-1/PD-L1-directed therapies. Additionally, only one approved therapy targets an immune checkpoint other than the PD-1/PD-L1 axis: the anti-CTLA-4 antibody ipilimumab. In recent years, it has become apparent that a panoply of additional signaling pathways modulate T cell activity, with distinct mechanisms outside the role of the PD-1 pathway in controlling ongoing localized inflammatory responses or the function of CTLA-4 in systemic self-tolerance. Some of these newly discovered checkpoints are already the target of numerous investigational agents in human trials and widely considered to be on the cusp of approval, as in the case of LAG-3.

Accumulated experience with the approved checkpoint inhibitors targeting the PD-1 axis has also enabled reverse translational studies that reveal new nuances of the immune landscape of the tumor microenvironment. In addition to the discovery of new co-stimulatory or co-inhibitory receptors and ligands, a prominent role for populations outside the lymphoid lineage has come to light in the activation or suppression of T cell responses, including the importance of innate immune cells and stromal cells for anti-tumor activity. Several of the novel checkpoints that have been discovered in recent years have also been demonstrated to play critical roles in innate-mediated anti-tumor immunity—an important and ongoing area of study for the immunotherapy field. 

Translating observations from pre-clinical models into usable therapies is not without challenges, however, and several investigational agents targeting novel immune checkpoints have, to date, yielded disappointing responses as monotherapies in randomized trials. Yet ongoing studies show hints of promising synergy between existing PD-1/PD-L1-targeting therapies and agents targeting novel checkpoints. Intriguingly, some new agents have demonstrated activity in tumor types generally thought to be weakly immunogenic, suggesting that expanding the repertoire of immune checkpoints could open up new settings amenable to immunotherapy.

Although the clinical development process for novel drugs may seem slow, especially in light of the urgent need for effective therapies for all-too-many still-lethal cancers, checkpoint inhibitors beyond anti-PD-1/PD-L1 agents are poised for a breakthrough. Industry has placed large bets on emerging checkpoints such as LAG-3, TIM-3 and TIGIT, and academia continues to advance the research pipeline.

This review series supports the ongoing momentum for investigation and clinical development of immune checkpoints therapies beyond the PD-1 axis. The articles highlight all aspects of the translational research pipeline—including pre-clinical rationale for novel targets, ongoing human studies, and high-level considerations for trial design. Readers from across the clinical-translational research enterprise will find value in these exceptional reviews. It is an exciting time for immunotherapy, and, with JITC, we are proud to move the field forward in this promising new direction.

Best Regards,

 

Ana Carrizosa Anderson, PhD    
Series Editor                 

                                               

Dario A.A. Vignali, PhD
Series Editor                                                                                                     

JITC Letter From the Editor - August 2020

Dear JITC Readers,

Welcome to this latest edition of the JITC digest. The papers highlighted this month offer exciting perspectives on the current state of the immunotherapy field as well as promising future directions for research.

 

Clinical oncologists can find a comprehensive overview of approved and emerging immunotherapies for multiple myeloma, including some of the new CAR T cell therapies currently in development, in the newest clinical practice guideline from SITC, by Nina Shah et al.

 

Promising clinical data on the use of checkpoint blockade for prostate cancer is provided in an original research article by Julie N Graff et al. The paper is the first to demonstrate durable responses with PD-1 inhibition in a subset of prostate cancer patients.

 

The identification of biomarkers to predict response to immunotherapy remains an important and ongoing area of study for our field. Two papers in this month’s digest highlight the key role that tumor metabolism plays in determining outcomes after immunotherapy, offering potential biomarkers for future study.

 

David Chardin and colleagues identify tumor metabolic parameters as measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) that are prognostic and predictive for outcomes after anti-PD-1 therapy for non-small cell lung cancer. Another immunometabolic biomarker is identified by Fangming Liu et al, who identify an association between FABP5-positive tumor infiltrating T cells and improved overall and recurrence-free survival in hepatocellular carcinoma.

 

New immunotherapeutic targets is another high-priority topic for research, and Marta Trüb and colleagues demonstrate promising in vitro anti-tumor properties with a novel fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL).

 

Finally, do not miss an excellent review by Christopher A Chuckran et al of Neuropilin-1, which acts as a receptor ‘hub’ for sorting signals from diverse ligands to both promote regulatory T cell (Treg) stability in the tumor microenvironment and inhibit anti-tumor CD8+ T cell responses—the latest in the Immune Checkpoints Beyond PD-1 review series.

 

As always, you can also further your reading with highlights from other journals in JITC’s Reading List, selected this month by Claudia M Palena, PhD, of the NCI.

Best regards,

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

To view the entire August 2020 JITC Digest, please click here. 

JITC Letter from the Editor - April 2020

Dear JITC Readers,

Even as the COVID-19 pandemic continues to challenge almost all aspects of daily life, JITC remains unwavering in our commitment to publishing the very best that the immunotherapy field has to offer. Although SARS-CoV-2 is radically changing how we as a community care for our patients and conduct our research, you can count on JITC as a constant source for new findings and important insights from across the spectrum of immuno-oncology. 

This month, the JITC digest offers several papers that develop intriguing strategies to boost antitumor immune responses. Jahangir Ahmed and colleagues engineered a replication-competent oncolytic vaccinia virus that delivers IL-12 to the tumor microenvironment, prolonging survival and controlling lung metastases when administered as an adjuvant to surgical excision in mouse models. Modulation of the tumor microenvironment also synergized with checkpoint blockade in a paper by Lucas A. Horn et al., where combined inhibition of TGF-beta and IL-8 signaling attenuated epithelial to mesenchymal transition in models of both breast and lung cancer. Additionally, Yong Li and colleagues revealed a key role in signaling through the innate immune danger-recognition sensor RIG-I in the development of interferon resistance in melanoma tumor-regenerating cells, identifying STAT3 as a potential therapeutic target. 

Also this month, in a paper that will surely prove reassuring, Nicholas Bevins and colleagues rigorously analyzed the impact of different methods of calculating tumor mutational burden and found good correlation between approaches. 

Finally, be sure not to miss an outstanding review by Lorenzo Galluzzi et al. that delivers a thorough overview of immunologic cell death with detailed discussions of the biological mechanisms leading to the establishment of immunologic memory, the available assays to measure key phenomena, and the hurdles to overcome for translation into clinical benefit. 

Best regards,

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

To view the entire April 2020 JITC Digest, please click here. 

JITC Letter from the Editor - March 2020

Dear JITC Readers,

The COVID-19 pandemic is a global emergency of unprecedented scale, placing an incredible burden on the healthcare system in every affected nation. As JITC readers, you are at the forefront of the outbreak, and, on behalf of the journal as well as SITC as a whole, we wholeheartedly offer gratitude for your ongoing efforts while wishing health and safety for you, your families and your patients.

Publication at JITC continues with this March edition of the JITC digest, which spotlights our commitment to publishing high quality scholarly work in a variety of formats. The journal is quickly becoming not only a leading repository of original research papers in the immunotherapy field, but also a go-to source for top-tier reviews and cutting-edge short hypotheses and case reports.   

Original research articles in this month's JITC digest are similar inasmuch as they describe processes for building tools, but they originate from opposite ends of the translational research spectrum. In a fully computational work that performed all experiments in silico with publically available datasets, Jie Sun and colleagues identify a long non-coding RNA signature as an indicator of immune cell infiltration in non-small cell lung cancer that was predictive of patient outcomes and response to checkpoint blockade. The other paper, from Ssu-Hsueh Tseng et al., describes extensive and elegant "wet" lab work to develop and validate a novel genetically induced mouse model of peritoneal metastasis in high-grade serous carcinoma.

Publishing excellent reviews is a priority for the journal, and we're proud this month to feature a comprehensive discussion of adenosinergic signaling in tumor immunosuppression with a focus on the potential of CD39 as a potential target for checkpoint therapy by David Allard, Bertrand Allard and John Stagg. This is part of JITC's growing Immune Checkpoints Beyond PD-1 review series.  

Finally, Esther Lutgens and Tom Seijkens present a hypothesis that checkpoint inhibition could promote the inflammatory processes in the vascular wall that drive atherosclerosis progression—a concept that merits further study.

As JITC continues to grow and thrive, the efforts and insights of the journal's peer reviewers are always appreciated. It's this "behind the scenes" work that ensures JITC remains the leading journal in the immunotherapy field. If you would like to support the journal while also gaining the many benefits of being a peer reviewer, we are welcoming applications, which you may submit through the SITC Volunteer Portal.

Best regards,

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

To view the entire March 2020 JITC Digest, please click here. 

JITC Letter from the Editor - February 2020

Dear JITC Readers,

Welcome to the February edition of the JITC digest. The journal continues to grow and thrive, publishing impactful research across the entire spectrum of the diverse and interdisciplinary immunotherapy field. The articles in this month's digest highlight innovative approaches to overcoming longstanding challenges in cancer immunotherapy, and will surely spark important conversations moving forward.

I'm thrilled to report that this month's digest features three papers from one of the journal's new sections, Immune cell therapies and immune cell engineering—a burgeoning area that continues to push boundaries in terms of advancing scientific understanding and improving patient outcomes.

The highlighted articles feature somewhat "outside-the-box" cell therapy strategies, two of which could have exciting implications for the treatment of solid tumors. In elegant preclinical models, Rahul Suresh et al. demonstrate robust anti-tumor activity by adoptively transferred gene-edited immature myeloid cells. In a different tactic, the feasibility of generating PD-1-deficient effector memory T cells specific for melanoma antigens was demonstrated by Lucine Marotte and colleagues.

Although cell therapies have a well-established role in the treatment of hematologic malignancies, relapse remains common. In an attempt to improve outcomes, Benjamin Derman et al. demonstrate two effective strategies to significantly reduce and delay T regulatory cell recovery after autologous stem cell transplant in a pilot study of 15 patients with multiple myeloma.

In addition to the exciting articles in the cell therapy section, be sure to read the paper by Shibin Qu et al., describing a novel approach to tumor ablation that causes the release of non-denatured neoantigens and damage-associated molecular patterns capable of potentiating the efficacy of checkpoint blockade for non-immunogenic tumors in mouse models.

Our field keeps moving at a tremendous pace! If you'd like to join in to real-time conversations about the latest research and you're active on social media, be sure to take a moment to follow the official JITC Twitter handle, @jitcancer.  

Best regards,

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

To view the entire February 2020 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 - 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. 

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]

Cancer: A Genetic and Immunological Disorder

by Praveen Bommareddy

Goal: The primary goal of my blog series is to contribute to SITC’s mission in educating patients, clinicians, and researchers about the recent advancements in immunotherapy. I am particularly interested in the use of genetically modified (non-pathogenic) viruses as immune modulators for cancer treatment. 

In this introductory edition of my blog series, I would like to provide an overview of cancer immunotherapy and a brief description on why immunotherapies may not always work well due to heterogeneity in tumor phenotypes and various mechanisms that suppress immune response against cancers.

Target audience: Patients and their families, clinicians, and researchers.

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.