Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer
To view the entire April 2021 JITC Digest, please click here.
I hope you enjoy this latest edition of the JITC digest. You are receiving this email after the conclusion of SITC’s 35th anniversary Annual Meeting and Pre-Conference Programs, this year re-imagined as an entirely virtual experience. Although we sorely missed the opportunity to interact with our colleagues in person, the virtual platform was an amazing opportunity for participants from around the world to experience the latest and greatest in immunotherapy research. Hopefully, you had an opportunity to stop by the virtual JITC booth during the meeting!
Included within the highlights of the meeting was the presentation of the annual JITC best paper awards. This year, the manuscripts honored were, “CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma” and “Mechanisms regulating PD-L1 expression on tumor and immune cells.” Of course, the award selection was a difficult decision this year, as JITC is blessed with an abundance of excellent papers, which is truly a “problem” that the journal is lucky to have as we continue to grow and expand.
Among the many important manuscripts published this month is “The Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of acute leukemia,” which is sure to be a valuable resource for the hematology-oncology community.
The rest of the papers in this month’s JITC digest touch on some hot topic areas in immunotherapy—myeloid cells, metabolism and novel targets, among others—inching the field forward to the overall goal of identifying and expanding the population of patients who may benefit, while revealing new insights into the mechanisms of actions of some familiar agents.
Hongfei Wang et al look beyond the traditional T cell-centered view for immuno-oncology and developed a novel myeloid-targeting agent that showed robust synergy with radiation in mouse models.
Blood-based biomarkers for response to checkpoint blockade have long been elusive, but Alissa Keegan and colleagues make use of ultrasensitive single-molecule array technology to identify a familiar cytokine—IL-6—as a potential factor with predictive value for survival benefit after PD-1 blockade.
New nuance in the T cell physiology associated with checkpoint blockade efficacy is provided by Hannah S Newton et al, who perform elegant electrophysiology experiments to identify distinct differences in voltage-gated ion channel activity, calcium flux and chemotaxis in blood- and tumor-infiltrating lymphocytes among patients with pembrolizumab-responsive and non-responsive head and neck cancers.
Potential utility for PI3Kdelta inhibition beyond hematologic malignancies and in solid tumors is demonstrated by Sarah Nicol Lauder and colleagues—intriguingly, they show that combination with anti-LAG3 therapy leads to even more pronounced effects, highlighting the promise of combinatorial approaches for novel immunotherapy targets.
Finally, do not miss an exceptional review by Maria Zagorulya, Ellen Duong and Stefani Spranger, discussing the implications of tissue-specific variability in myeloid cells on the efficacy of checkpoint blockade therapy.
Welcome to the latest edition of the JITC digest. For many of our readers, especially in the United States, October is associated with Halloween—the seasonal mood hearkens back to the earliest days of immunotherapy, when many considered the concept of immunological control of tumors to be the stuff of “witchcraft.”
Now, of course, thanks to tireless efforts by clinicians and researchers as well as participation by patients in clinical trials, our understanding of tumor immunology has advanced by leaps and bounds. Concepts once thought to be spooky and mysterious such as immune checkpoints are now generally accepted as common knowledge. Every advance, however, also brings new areas of inquiry, and JITC will continue to publish the leading research in our field. The JITC’s corrected Impact Factor just released by Clarivate Analytics of 10.252 attests to the growing influence of the journal in a field that has taken center stage in oncology and immunology.
We also look forward to SITC’s annual meeting and pre-conference program, this year reimagined as an entirely virtual experience. The virtual meeting will be a one of a kind opportunity to hear from luminaries in our field as well as view presentations on the latest research. Find out more about registration here.
The original research articles featured in this month’s digest highlight several exciting emerging areas in immunotherapy. Elham Beyranvand Nejad and colleagues add a new angle into the important topic of mechanisms of immunotherapy resistance, with an in-depth characterization of the importance of the myeloid cellular component in the tumor microenvironment for preventing recurrence.
Efficient targeting of regulatory T cells in the tumor microenvironment has had limited success to date, but Francesca Zammarchi et al provide promising pre-clinical evidence that a CD25-directed antibody-drug conjugate may efficiently deplete immunosuppressive cells and strongly synergize with checkpoint inhibitors, allowing for robust disease control.
In an outside-of-the-box approach to improve yields for chimeric antigen receptor T cell manufacturing, Andrea Schmidts and colleagues developed artificial antigen presenting cells that improve over conventional bead-based reagents for T cell activation in several aspects. Of note, Schmidts et al modified the artificial antigen-presenting cells to disrupt expression of the lentiviral binding receptor and avoid “vector sink” during transduction using CRISPR-Cas9—the technology honored with the 2020 Nobel Prize in chemistry.
Immunotherapy in the neoadjuvant setting is an important and ongoing area of research. Although the trial of nivolumab and ipilimumab prior to surgery for resectable non-small cell lung cancer reported by Joshua E Reuss and colleagues was prematurely terminated due to toxicity, the findings underscore the importance of future research, especially on biomarkers to predict response to treatment.
Finally, in addition to the excellent original research in this month’s digest, it’s a pleasure to spotlight a review from the recently completed series on immune checkpoints beyond PD-1. If you have not read these outstanding reviews, be sure to browse the entire collection, in addition to the overview of TIGIT in immunotherapy highlighted in this month’s digest.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,
Dario
A.A. Vignali, PhD
Series Editor
Tel: +1 414 271 2456 | Fax: +1 414 276 3349 | Email: info@sitcancer.org