Letter From the Editor- March

Dear JITC Readers,

Welcome to this month’s edition of the JITC digest. For many of our American and European readers, March marks the one-year anniversary of the first local shelter-in-place orders and travel restrictions in response to the COVID-19 pandemic.

 

Although everyday life is still far from the pre-pandemic normal in many places, it seems as though the news has been increasingly hopeful day-by-day, especially as the pace of vaccination continues to accelerate.

 

We in the immunotherapy community can share in some of the pride in the outstanding success of the RNA-based COVID vaccines—as JITC readers are well aware, the platform was originally developed for anti-tumor therapy. Additional intersections between cancer immunotherapy and SARS-CoV-2 will be explored in JITC’s new COVID-19 and Cancer Immunotherapy Review Series.

 

RNA vaccines are but one of many examples of innovations that originated in the immunotherapy field with far-reaching implications. Our discipline excels at developing new platforms, and there is no shortage of interesting technologies to be found in this month’s original research articles. As an example, be sure to read about the use of virtual clinical trials to optimize dosing schedules for combination oncolytic virus therapy in an intriguing computational biology paper by Adrienne L. Jenner and colleagues.

 

We have a wealth of biomarkers papers this month, all of which not only describe novel observations, but also rigorously provide mechanistic insight into tumor immunobiology. In one such report, Jiakai Hou et al elegantly leverage published data sets combined with a well-designed CRISPR/Cas9 drop-out screen to identify and categorize tumor-intrinsic resistance mechanisms to immune elimination.

 

Retrospective analyses also yield new insights in a paper by SIyuan Dai and colleagues, who identified in silico and validated in vitro a role for CD8+ T cell-secreted CXCL13 in immunoevasion by clear cell renal cell carcinoma.

 

A different chemokine’s receptor, CCR8 is revealed to be a specific marker of intratumoral regulatory T cells and a viable immunotherapeutic target that yields tumor control without autoimmunity in murine models in a manuscript by Helena Van Damme et al.

 

Finally, Karen Slattery and colleagues identify a novel, targetable and prognostic autocrine regulatory circuit involving TGF beta that leads to systemic natural killer cell dysfunction in patients with breast cancer.

 

Although many of us have been physically distanced from each other for much longer than we’d like, it is clear that our community of JITC readers, authors, editors, and reviewers is as strong and vibrant as ever, and I look toward the future with optimism.

 

Best regards,

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

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

President's Message -- February Fireside Chat with BioNTech CEO Ugur Sahin, MD

 Dear Colleagues,

One of my hopes over the next two years as your society President is to have sit-down conversations with some of the leading experts in cancer immunotherapy, and even potentially, the greater global scientific field. These “fireside chats” will seek to celebrate the work accomplished by the individual (and his/her team) in cancer research, and discuss the ornate hurdles that remain present to any number of challenges in their line of work.

This month, I am extremely pleased to welcome SITC member, Ugur Sahin, MD. CEO of BioNTech SE, Dr. Sahin and his company collaborated with Pfizer Inc., to produce and receive emergency use authorization for a SARS-CoV-2 vaccine in record time. I spoke to Dr. Sahin this month, in my first fireside chat, to discuss his background as an academic professor and researcher, the obstacles his company has had to overcome to develop an extremely effective vaccine and his expectations for the months ahead as a billion or more humans seek to receive protection from this virus.

I’m featuring a portion of the Q&A below for this month’s President’s Message, but please visit SITC’s COVID-19 Resources page on SITC CONNECT to watch the entire discussion.

Click here to watch the full interview

 

Question: How did you get this vaccine to U.S. FDA (emergency use authorization) in less than a year? Even the experts everywhere were saying it would take three to five years to get a vaccine initially, and here you did it in 11 months. How did you get that done?

Dr. Sahin: When we started our project, we expected this would really become a global pandemic. Our goal from the very beginning was to develop a vaccine and make it available in less than one year. We named our project Lightspeed, and the idea behind this designation was that we should not lose any time, so we did not have time to waste.

We implemented a 24/7 research program. When we started, we did not know what the best vaccine candidate was, so we started with 20 vaccine candidates. We did the full pre-clinical testing immunogenicity operation of these candidates. We even GMP toxicology study, because this was a pre-requisite from the Paul-Ehrlich Institute to evaluate that. We did the GMP manufacturing, and then we started the program just a few days later.

We submitted our documents on April 20 and three days later we had the approval to start the clinical trial in Germany. We did a partnership with Pfizer. Our plan was to have a serious approach to get all of the immunogenicity data from Phase 1. We understood that two vaccines provided really strong antibody and T-cell responses. We made the decision on July 24 for one of the candidates, and on July 27 the Phase 3 clinical trial started.

Question: What’s the future hold for RNA vaccines and infectious disease? Do you see that this technology is going to start to take over, and how many different epitopes can you put in there? Do you think you’re going to one day make a COVID-flu combination vaccine for example?

Dr. Sahin: The technology has extremely broad versatility, so you can combine. In our cancer trials, we are already combining four antigens, or six antigens. And this is of course possible in the same way for infectious disease vaccines. You can combine several antigens for one virus or combine antigens for different viruses.

Another key advantage of mRNA is to be able to make faster vaccines, so the manufacturing itself takes less than two weeks, then we have about two additional weeks for quality control and sterility testing, so that means you can in principle deliver a vaccine, from scratch, within four to six weeks. This is of course important advantages compared to the viral vector vaccines or the recombinant protein vaccines.

Question: How long do you think people will be immune for after having taken an RNA-based vaccine? Do you know from your cancer studies, can you predict with the COVID vaccine, is it going to be years?

Dr. Sahin: In principle we have to ask the question in different ways. The first lesson is what is needed to avoid infection at all? The prediction here is to avoid infection, you would need higher neutralizing antibodies, which are the key to avoiding infection. If you ask the question how long is protection for avoiding severe disease, this will be much longer. Avoiding severe disease can already be happening by having sufficient number of memory cells so that the immune response can kick on early, and even if you get infected, it’s not as severe disease because the immune system can catch up and control the virus infection in a few days. I think this is the way how vaccines work – if the immune response is quick, it can prevent severe disease; if the immune responses is very strong it can prevent infection.

Here at the moment in the pandemic situation, we are of course interested in both. First of all we would like to prevent infection, because if we prevent infection we will also prevent transmissions. But the second best thing we can do is prevent severe disease and thereby avoiding people dying from the infection. The latter could be accomplished, if the goal is the latter, then I believe such vaccines could have a memory effect for years. If we really want to avoid infection, then every year a booster might be useful.

 It was a very enjoyable and thought-provoking conversation, and I am very thankful for Dr. Sahin for his eagerness to share his experiences and lessons learned thus far from developing the coronavirus vaccine. I hope you enjoy listening to the entire discussion on the SITC website, and I look forward to other engaging fireside chats with cancer leaders in the future!

Sincerely,

 

Patrick Hwu, MD

SITC President

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.