JITC Letter from the Editor - December 2019

Dear JITC Readers,

This is the final JITC digest of 2019, and we are ending the year on a historic note with December’s issue containing the most-ever papers published in a single month since the journal’s inception! It has been an exciting year for JITC, and we look forward to what the future holds as the immunotherapy field continues to expand and evolve.

The highlighted papers in this month’s JITC digest truly exemplify some of the most exciting areas of research in our field, spanning preclinical models to human trials and adding new insight into the contribution of the tumor microenvironment to disease progression and immunotherapy resistance as well as the development of novel immunotherapeutic agents.

Be sure to read the Editor Picks below about microenvironment-targeting therapeutics for the reprogramming of myeloid-derived suppressor cells and for the selective depletion of tumor-associated macrophages, gene-edited “off-the-shelf” CAR T cells for the treatment of glioblastoma, preclinical validation for a new checkpoint inhibitor target in ovarian cancer, newly described mechanisms of immunotherapy resistance in melanoma, a deeper understanding of the two types of secondary bone metastases in prostate cancer, and a phase 2 trial describing dendritic cell vaccines for prostate cancer that that induce clinically meaningful immune responses.

With best regards,

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

To view the entire December 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. 

President's Message - July 2018

Dear Colleagues,

Let me begin by congratulating everyone who contributed to the exciting achievement of the Journal for ImmunoTherapy of Cancer (JITC), the Society for Immunotherapy of Cancer's (SITC) open access, peer-reviewed online journal, on its first impact factor of 8.374!

As many of you know, an impact factor – a calculation of the number of citations a publication's articles received in a year by the total number of articles published – quickly communicates to prospective authors the reach and quality of research a publication possesses. The JITC impact factor is the next big step toward an even brighter future for our society's online publication.

Much of the credit goes to JITC Editor-in-Chief Pedro J. Romero, MD, and the many SITC member experts who serve as section editors and reviewers on the journals' Editorial Board. However, JITC would not be what it is today – or further, what it is becoming – without the contributions from the many authors who have submitted their field-changing research to JITC.

Now, five years after our society's launch of JITC, this achievement provides significant validation to the journal as a premier destination for cancer immunotherapy research. I encourage all prospective authors in our field to submit to JITC when considering a venue for your work.

Among the most valuable of JITC's publications are the consensus statements submitted as part of the SITC Cancer Immunotherapy Guidelines. These immunotherapy treatment recommendations play a critical role in educating oncologists and other members of the patient care team on current standards involving U.S. Food and Drug Administration-approved cancer immunotherapy treatments for a growing list of disease states. SITC expanded its Cancer Immunotherapy Guidelines offerings in May when it updated its recommendations on cutaneous melanoma. A manuscript on non-small cell lung cancer is slated to publish in JITC next month.

We're also disseminating these guidelines broadly to increase access. This includes a new, interactive series of SITC Cancer Immunotherapy Guidelines Webinars. These live events will take place approximately two months after manuscript publication and will allow authors to go further in-depth about the treatment recommendations, answer questions and discuss any late-breaking advances in the field since publication.

The first SITC Cancer Immunotherapy Guidelines Webinar will take place Monday, July 30, 6–7 p.m. EDT, focusing on the recent update of the guidelines for cutaneous melanoma. Click here to register for this free opportunity.

The need for ongoing education for clinicians about the latest advancements in immunotherapy for cancer has never been greater. At the American Society of Clinical Oncology's (ASCO) 2018 Annual Meeting, SITC staff fielded numerous questions from attendees, and served as a resource to many visitors of our society's booth at ASCO 2018. If you would like to review highlights of the meeting, SITC published daily scientific reports from the ASCO Annual Meeting, log in to your SITC CONNECT account to access our staffreports from each day of the meeting.

In closing, as you enjoy a little lull in your scientific activities over the summer, and write up the results of your recent studies, I hope you will send those data to JITC, where the new 8.374 impact factor will assure great exposure to your colleagues.

Sincerely,

Lisa H. Butterfield, PhD

SITC President

Staying Alive: My IO Journey

by Jacqueline Smith

On Nov. 29, 2006, during the first semester of my graduate school program, I learned the disease I thought I had beat three years prior had, again, reared its ugly head. I was devastated. The lump I had detected in my bikini line almost a year-and-a-half earlier was not the inflamed lymph node that my gynecologist assured me it was, and it was not the result of some minor infection that my primary care provider’s assistant diagnosed. It was a lymph node filled with cancer.

Upon my diagnosis three years earlier, I was advised by my then oncologist to “watch and wait” because the treatments at that time were highly toxic causing debilitating and irreparable long-term damage. However, this time, watch and wait was not an option.

Jacqueline Smith

I returned to my parent’s home in Orlando, Fla. I visited a number of doctors and specialists. On Dec. 21, 2006, I was told it would be a miracle if I survived another five years. Needless to say, I spent the holiday season drowning in self-pity and worry mixed with anger and resentment.

Though none of us know when we will reach the end, most live everyday with the promise and hope for a new day. However, receiving a cancer diagnosis quickly forces one to face their mortality.

Fortunately, with the New Year came new resolve. I was not going to abandon my dreams. I was not going to let this disease consume every aspect of my life. I decided to fight. I began to research every aspect of melanoma: the disease, surgeries, treatments, treatment centers and specialists.

Every doctor whom I contacted recommended I seek treatment at the H. Lee Moffitt Cancer Center in Tampa, Fla. It was there I was given hope. My surgical oncologist stated that while he could not determine my life expectancy, if I did not have the cancerous lymph nodes removed, there was a high possibility that cancer (melanoma) would kill me. He also expressed hope that I would qualify for a clinical trial.

On March 29, 2007, I had a total right groin lymphadenectomy. It was then that Dr. Vernon Sondak alerted me to a newly opened clinical trial. It was then that I learned what immunotherapy was and decided to rest my fate in its hands.

I became one of the first enrollees in the PEG-Intron trial. For the first three months, I had to go to Moffitt daily, for blood draws. I learned to mix and self-administer the Pegylated interferon. I was encouraged to learn this treatment was less harsh than chemotherapy. I was thankful that I would be able to an outpatient during my care.

Most importantly, I no longer thought about my mortality, but rather focused on my treatment and the potential for being cured.

I endured surgery, PEG-Intron therapy and four months of radiation.

Today, 10 years later, I am thankful to say I am cancer free. As my 10-year, cancer-free survival is due, in part, to the success of an immunotherapy clinical trial, I have decided to dedicate my life to working toward establishing immunotherapy as a standard of care for all cancer patients.

I am now the Policy and Advocacy Manager for the Society for Immunotherapy of Cancer (SITC). At SITC, I am one of many people who work tirelessly to advance the field of immunotherapy in hopes of helping more cancer patients enjoy a better quality of life and transition from long-term cancer free survival to being cured.

President's Message – June 2018

Dear Colleagues,

As summer begins, I am happy to share news about a number of SITC initiatives that our members are involved in, addressing important aspects of our field.

First, I would like to congratulate members of the SITC Immunoscore Validation Project – whose Steering Committee is Chaired by Past SITC President Bernard A. Fox, PhD – on the recent publication of its study's findings in The Lancet. Involving tissues banked from more than 3,500 patients and more than a dozen SITC member volunteers across 13 countries, the study showed that the Immunoscore measures of stage I-III colon cancer patients positively correlated with survival and time to recurrence. I highly recommend that you read this important publication.

Second, I would like to commend the work of the SITC Cancer Immune Responsiveness Task Force and Immune Biomarkers Committee for their effort in hosting a pair of SITC workshops earlier this month in San Francisco. More than 200 attendees contributed to discussion around the current major questions in our field which will lead directly to new initiatives for the society in these areas. Attendees also developed new collaborations to move the field forward. Stay tuned as these new initiatives are announced, and materials from these workshops become available to members and the general public later this month.

Third, I want to share the news that our highly anticipated Cancer Immunotherapy Guidelines for cutaneous melanoma update published on Wednesday! First published in 2013, these clinical guidelines serve to educate a clinical audience on a disease state that was among the first to achieve significant progress via cancer immunotherapy for patients. Thank you to the Cancer Immunotherapy Guidelines Cutaneous Melanoma Subcommittee for your major commitment to this effort! This melanoma manuscript is the first in our society's series of Cancer Immunotherapy Guidelines to receive an update. New guidelines in non-small cell lung cancer and head and neck cancers will publish this year in our society's Journal for ImmunoTherapy of Cancer (JITC).

Another way that SITC seeks to improve our field's future is through the SITC Sparkathon. Young investigators can apply now to participate in the SITC Sparkathon Class of 2018. This team science opportunity, which will last 12-18 months, forges new collaborations among the field's brightest early career scientists as they seek to solve an existing obstacle. These scientists will receive valuable professional development from top business coaches and SITC leadership. Applications are due by 11:59 p.m. EDT on Monday, June 18.

The inaugural SITC Sparkathon Class of 2017, teams TimIOs and METIOR Incubator, will present their projects during the 33rd Annual Meeting this November.

Very soon, our society members will elect a new Vice President in the upcoming annual election. From June 14–28, the 2018 SITC Election will include the Vice President position and three At-Large Director openings on the Board of Directors. Learn more about this year's candidates, who are also listed below, and please remember to vote (online voting begins June 14).

Finally, I am happy to share that current registration numbers confirm our expectations that SITC 2018 will be our society's most highly attended yet! Register now to attend SITC 2018 and secure your housing. Also, don't forget the deadline to submit regular abstracts, late-breaking abstract applications or applications to the Immune Escape program is 5 p.m. PDT on Aug. 1.

I'm looking forward to seeing you all at the Walter E. Washington Convention Center in Washington, D.C. this November!

Sincerely,

Lisa H. Butterfield, PhD

SITC President

Focused Radiation May Help Turn on the Immune System

Focused Radiation May Help Turn on the Immune System

by Christian Hyde, MD

Radiation given in combination with immunotherapy can potentially kick-start an exhausted immune system. This has been most famously observed in a melanoma patient on Ipilimumab, published by Dr. Michael Postow and others in the New England Journal of Medicine. At first, the ipilimumab worked, and her tumors shrank. Then the tumors developed resistance and regrew. By radiating one of her tumors near the spine, with 3 large doses of radiation, her immunity was restored, and all her tumors shrank, not just the irradiated tumor. The combination increased tumor specific T-cells and antibodies.

The result has a scientific nickname: the abscopal effect, derived from a combination (aptly enough) of two words—ab, for “away,” and scopus, for “target.” The effect, first reported about 50 years ago, is currently rare, seen in a small number of patients who undergo radiation therapy for metastatic disease.

Radiation doses of 8 to 10 Gray appear to be ideal to wake up the immune system and cause the tumor to become inflamed such that it is fertile ground for immune activity. Recent work by Dr. Silvia Formenti and others has shown that these high doses of radiation makes cancer cells look and act like virus-infected cells. The radiated cancer cells produce interferon and display more surface antigens, helping to target themselves for immune destruction, using many of the same pathways as a virus-infected cell. 

The abscopal effect is rare because radiation also simultaneously increases the production of inhibitory blomolecules and regulatory T-cells, which stop killer T-cells from overdoing their job. The same processes that activate the immune system thus control how far it can spread, shutting down the immune response before it causes too much collateral damage in the body, keeping radiation responses local.

At least three key pathways have been shown to limit the spread of anti-tumor immunity after radiation:

1. Regulatory T-cells increase in response to radiation. These “Tregs” can be recruited by tumors to help protect tumor cells from immune destruction.
2. Programmed Death-Ligand 1, or PD-L1. Tumor cells increase this protein on their cell membrane in response to radiation, a change that can be detected on circulating tumor cells during a course of radiation therapy. This makes them resistant to CD-8 T-cell killing.
3. IDO-1 is an enzyme that is upregulated in tumor surroundings in response to radiation, which paralyzes killer T-cells crossing into the area, like soldiers getting stuck in a moat.

All three of these mechanisms were shown to be at work by Dr. Elena Muraro and others following 3 daily doses of 10 Gray each in breast cancer patients with up to 6 metastases irradiated. In theory, if a patient takes immunotherapy drugs like ipilimumab, nivolumab, and epacadostat during radiation, it may help deplete the Tregs, overcome PD-L1, and block IDO, respectively, allowing a local immune response to broaden to other metastases. 

Chemotherapy has taught us that multiple drugs, usually 4 or more with independent mechanisms, are needed before cure rates exceed 90%, such as ABVD for Hodgkin’s lymphoma. Blocking one resistance pathway is seldom enough, just like blocking one road into a city won’t stop all traffic; traffic simply increases on all the other roads. There are many available routes of immunity to regulate, including checkpoints, cytokines, antibodies, and cells. It’s probably not until we get multi-drug combinations, added to radiation, that the distant abscopal effect becomes a regular thing. In the meantime, the “adscopal”, or local synergist effects of radiation plus PD-1 inhibitors, are also showing promise.

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. 

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.

SITC 2017 Scientific Highlights - Nov. 11

The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the Saturday programs (Nov. 11, 2017) of the 32nd Annual Meeting in National Harbor, Md. (Scroll to the bottom of this blog post to view the Glossary).

Dendritic cell acquisition of MHC I controls CD8+ T cell priming

Brandon MacNabb, BS (University of Chicago) presented data supporting the concept of MHC I antigen presentation by Batf3-lineage DCs as a critical component of CD8+-mediated anti-tumor response. Researchers initially generated H2-KbAB (MHC I+) and Kb-/-(MHC I-) C1498.SIY acute myeloid leukemia cell lines and subsequently engrafted C57BL/6 mice to determine the contribution of tumor cell MHC I presentation in CD8+ T cell priming. Initial assessment revealed reduced tumor growth in C1498.SIY KbAB mice compared to C1498.SIY Kb-/- mice. CD8+ T cell proliferation was also increased in KbAB mice compared to Kb-/- mice (p < 0.05). The observed C1498.SIY KbAB-dependent CD8+ proliferation was abolished in Batf3-/- C57BL/6 mice (p < 0.01). IFN-ϒ secretion was also decreased in Batf3-/- KbAB mice, suggesting that Batf3 initiates CD8+ priming. Transfer of autologous T cells from KbAB tumor-bearing mice offered complete protection from tumor growth in tumor-free mice. Conversely, autologous T cells from Kb-/- mice offered no such protection. Interestingly, DCs isolated from the TME and the tumor-draining lymph node in tumor-positive mice had increased KbAB MHC I expression (p < 0.001), suggesting DC acquisition of tumor-derived MHC I. Ex vivo experiments confirmed that migratory KbAB DCs are capable of CD8+ priming. These data reveal the importance of Batf3-lineage DCs and tumor-derived MHC I presentation in CD8+ T cell activation of anti-tumor response, providing insight into potential development of DC-oriented therapies. 

SITC 2017 Scientific Highlights - Nov. 10

The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the first day of the 32nd Annual Meeting in National Harbor, Md. (Scroll to the bottom of this blog post to view the Glossary)

Co-administration of novel anti-sMIC antibody increases anti-CTLA-4 therapeutic response in TRAMP/MIC mice (O22)

Jennifer Wu, PhD (Northwestern University, Chicago, IL) presented recently-published data investigating the efficacy of a novel antibody targeting the highly immunosuppressive human activation immune receptor natural killer group 2D (NKG2D) ligand, sMIC, with the goal of increasing anti-CTLA-4 therapeutic response. Using a TRAMP (transgenic adenocarcinoma of the mouse prostate)/MIC mouse model, Wu’s group found that mice with increased circulation of tumor-derived sMIC receiving anti-CTLA-4 had ~25% decrease in survival over 8 weeks compared to mice receiving placebo (p < 0.05), as well as an increased risk of immune-related colitis. TRAMP/MIC mice receiving anti-CTLA-4 in combination with anti-sMIC had reduced prostate tumor burden (~0.25g vs ~6g, respectively; p < 0.001), increased DC activation, enhanced TCR/CD3 signaling, and increased T cell clonality in tumor infiltrates compared to mice receiving anti-CTLA-4 alone (P < 0.05). CR was observed in 4/5 combination-treated mice for at least 120 days post-therapy, with no cases of immune-related colitis. These pre-clinical anti-sMIC/anti-CTLA-4 data align with clinical observations in patients with mCRPC, melanoma and multiple myeloma who have demonstrated improved responses to anti-CTLA-4 therapy if they develop sMIC autoantibodies during the course of treatment. These results suggest that sMIC may act as a predictive biomarker for anti-CTLA-4 response. Furthermore, including anti-sMIC antibodies in CTLA-4-targeted therapies may reduce irAES and increase treatment efficacy.