JITC Letter From the Editor -October 2020

Dear JITC Readers,

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.

 

Warm regards,

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

To view the entire September 2020 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                                                                                                     

President's Message - October 2020

Dear Colleagues,

Our society continues its preparations toward our fully virtual 35th Anniversary Annual Meeting & Pre-Conference Programs (SITC 2020), scheduled for Nov. 9–14, 2020. Please take note that the SITC 2020 meeting registration fee has been waived for ALL SITC members. You can become a member or renew your membership during the SITC 2020 online registration process.

Also, to accommodate for the COVID-19 impact on cancer immunotherapy research this year, the late-breaking abstract (LBA) submission period will be opened to everyone. SITC will not require an LBA application to be submitted beforehand. Previously submitted LBA applications will automatically be invited to submit a full LBA during the LBA submission period, Sept. 8-22, 2020, at 5 p.m. PDT.

In addition to the intense preparations for the Annual Meeting, the Society for Immunotherapy of Cancer continues to make progress on its objectives for this year. Educating clinicians on all aspects of cancer immunotherapy is one of our main objectives and directly serves the goal of improving patient outcomes. This past month the Certificate in Cancer Immunotherapy Program was launched, and is being offered online via our society’s SITC Cancer Immunotherapy connectED platform. The SITC certificate consists of eight learning modules all of which offer relevant education credits (CME, CNE, CPE and MOC).  After successful completion of the modules, the SITC Graduate in Cancer Immunotherapy (SITC-G) designation is granted and identifies a healthcare provider who has completed specialized training in cancer immunotherapy.

The first of eight modules, presented by Robert Ferris, MD, PhD (Director of the University of Pittsburgh Medical Center Hillman Cancer Center, long-time SITC member and past At-Large Director), is now online. It covers basic concepts of immunology, including innate and adaptive immune responses. The other seven module topics, which will be launched in the weeks ahead, include:

• Basic Cancer Immunotherapy Concepts
• Immune Checkpoint Blockade
• Managing Immune Checkpoint Inhibitor Adverse Events
• Other Approaches, including Cytokines, Vaccines, Immune Cell Engagers
• Oncolytic Viruses and Intralesional Therapy
• CAR T Cell and Cellular Therapy
• Implementing Cancer Immunotherapy in Clinical Practice

SITC executive leadership, faculty and staff have put many months of effort in the planning and continued execution of this exciting new SITC program. I would like to thank all of those involved in the Certificate in Cancer Immunotherapy program, including Executive Director Tara Withington, CAE, and Past President Howard L. Kaufman, MD, FACS, both of whom championed this effort and the need for such a program for multiple years.

To learn more about eligibility requirements to earn your Certificate in Cancer Immunotherapy, please click here. SITC members receive a 20 percent discount on all Certificate in Cancer Immunotherapy modules, so if you haven’t yet, please be sure to join the SITC family to take advantage of this exclusive member benefit.

Sincerely, 

Mario Sznol, MD

SITC President