SITC Meeting Report: April 29 FDA ODAC Summary

The Society for Immunotherapy of Cancer (SITC) is pleased to present this report on the April 29, 2021, meeting of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC).

Gastric and Gastroesophageal Junction Adenocarcinoma

In 2017, anti–PD-1 pembrolizumab was granted an accelerated approval for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (combined positive score [CPS] greater than or equal to 1) as determined by an FDA-approved test, and have failed two or more lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, human epidermal growth factor receptor 2 (HER2)/neu-targeted therapy. Approval was granted based on an observed 13.3% objective response rate (ORR) within Cohort 1 of KEYNOTE-059. However, both KEYNOTE-061 (second-line pembrolizumab vs. paclitaxel) and KEYNOTE-062 (first-line pembrolizumab in combination with 5-fluorouracil and cisplatin vs. chemotherapy alone) have failed to confirm an overall survival (OS) benefit of adding the PD-1 inhibitor to the treatment regimens for patients with PD-L1+ gastric or GEJ adenocarcinoma.

Pembrolizumab

On April 29, 2021, FDA ODAC met to discuss maintaining the indication for third-line pembrolizumab monotherapy for PD-L1+ patients with gastric or GEJ adenocarcinoma in light of currently available clinical trial data as well as the rapidly evolving treatment landscape for this patient population. The committee voted 6-2 to recommend rescinding the current indication.

Sponsor Position:

• Pembrolizumab monotherapy addresses a significant unmet medical need for treatment of heavily pre-treated patients who may not be able to tolerate chemotherapy
• Data provided by KEYNOTE-059 are consistent with data supporting alternative approvals in this patient population with a generally poor prognosis (ex. median OS is 6 months across clinical trials currently supporting treatment approvals)
• Pembrolizumab has an acceptable safety profile and is well tolerated in the third-line, PD-L1+ patient population
• By 2024, four ongoing clinical trials will provide data that may be able to confirm pembrolizumab clinical benefit in this patient population
• KEYNOTE-061 may not serve as appropriate comparisons for approval confirmation, as more recent data suggest earlier lines of gastric and GEJ treatment require chemotherapy addition
• KEYNOTE-590 data revealed an OS benefit of pembrolizumab addition to chemotherapy for the treatment of patients with esophageal or GEJ adenocarcinoma and supported FDA approval for first-line treatment

FDA Position:

• Recent approvals, including first-line PD-1 inhibitor nivolumab + FOLFOX or CAPEOX for patients with gastric and GEJ adenocarcinoma, may address the unmet medical need served by the discussed pembrolizumab indication
• ORR within the PD-L1+ patient population from Cohort 1 of KEYNOTE-059 may have been contaminated through the inclusion of patients with unknown tumor microsatellite instability/tumor mutational burden status
• Ongoing clinical trials by the sponsor evaluate pembrolizumab in combination with chemotherapy and are not assessing monotherapy as described within the current indication
• Given the low ORR demonstrated within KEYNOTE-059, the risk/benefit may not support approval given possibility of immune-related adverse events

Public Comment:

• This treatment addresses and unmet medical need for patients in third-line setting who have not received IO and those who cannot tolerate chemotherapy

Committee members cited currently available clinical trial data as not supporting the risk/benefit ratio of retaining the indication. They also noted that none of the currently ongoing clinical trials would serve to answer whether pembrolizumab monotherapy provides clinical benefit. Lastly, there was discussion on how recent first-line immunotherapy indications would likely become standard of care, and that future patients requiring third-line treatment may not be eligible for checkpoint inhibitor therapy. Given the recommendation to rescind the indication, committee members emphasized the importance of delaying any planned market removal to ensure that patients currently receiving the therapy could enter into an expanded access program or single patient IND to continue treatment. The FDA was in support of these measures and emphasized that they were cognizant of the impact upon patients if the indication were to be ultimately rescinded.

Hepatocellular Carcinoma

Anti PD-1 nivolumab, the first checkpoint inhibitor to be marketed for treatment of patients with hepatocellular carcinoma (HCC) whose disease progresses after treatment with the first-line vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) sorafenib, gained accelerated approval in September 2017. Approval was based on the results of one of the treatment arms of the multicenter, open-label, phase I/II trial CheckMate 040, which showed a confirmed ORR in this patient population of 14.3% (95% CI: 9.2, 20.8), with 91% of responders having responses lasting 6 months or longer and 55% having responses lasting 12 months or longer. A second anti-PD-1 agent, pembrolizumab, received accelerated approval for the same indication based on an independent central review-assessed ORR of 17% (95% CI: 11, 26) with 89% of responders having durations of 6 months or longer and 56% having response durations of 12 months or longer in the single-arm, multicenter, phase I/II study KEYNOTE-244.

Advanced HCC is associated with a very poor prognosis and the disease almost always develops against a background of cirrhosis, complicating therapy selection in patients with poor liver function and high burden of comorbidities. Since the initial accelerated approvals of pembrolizumab and nivolumab, the treatment landscape for HCC has changed, with the combination of the anti-PD-L1 atezolizumab plus the anti-VEGF bevacizumab attaining full approval for first-line treatment of HCC based on significant OS and PFS improvements in the multi-center, open-label IMbrave150 trial. However, up to 15% to 20% of patients with HCC cannot be treated with bevacizumab due to bleeding risk. Nivolumab in combination with anti-CTLA-4 ipilimumab also received accelerated approval for patients with HCC who have been previously treated with sorafenib in March 2020. This indication was not under consideration at this meeting.

Review of the HCC indications for nivolumab and pembrolizumab monotherapies was motivated by the low response rates in their respective registration studies as well as failure to verify clinical benefit in the designated confirmatory studies CheckMate 459, which did not meet efficacy thresholds for OS benefit in the first-line setting, and KEYNOTE-240, which did not achieve pre-specified statistically significant OS improvement in the identical to the registration trial post-sorafenib setting.

Pembrolizumab

On April 29, 2021, FDA ODAC voted 8 to 0 in favor of maintaining the accelerated approval of pembrolizumab for patients with HCC who have previously been treated with sorafenib. The unanimous decision was based on the substantial unmet need for second-line immunotherapy options in the population ineligible for bevacizumab treatment as well as the panel’s opinion that KEYNOTE-240 demonstrated clinically meaningful benefit despite not meeting pre-specified significance thresholds in OS.

Sponsor Position:

• Pembrolizumab monotherapy represents an important option for the significant proportion of patients with HCC who cannot receive first-line bevacizumab and whose disease progresses after sorafenib
• The incremental benefit of second-line pembrolizumab is analogous to the approved second-line TKIs, and the toxicities associated with pembrolizumab monotherapy are largely manageable
• Durable responses seen with pembrolizumab monotherapy are clinically meaningful

FDA Position:

• ORR with pembrolizumab monotherapy was low in the registration trial KEYNOTE-244 and the confirmatory trial KEYNOTE-240
• Recognizing that the bevacizumab-ineligible population represents a significant unmet need, patients at high risk for bleeding with bevacizumab were not included in KEYNOTE-244 and KEYNOTE-240

Public Comment:

• HCC is associated with very poor prognosis and significant unmet need, especially for the patients with poor underlying liver function or who cannot receive first-line atezolizumab + bevacizumab due to bleeding risk
• Removing options for second-line therapies is not in the best interest of patients with HCC

Alternative confirmatory trials for pembrolizumab have completed accrual and results are anticipated soon. Specifically, the final analysis of KEYNOTE-394, which is evaluating benefit in the post-sorafenib setting in an East Asian population is expected as early as June or July of 2021, and the results of the LEAP-002 trial comparing first-line pembrolizumab in combination with the VEGF-TKI lenvatinib to lenvatinib monotherapy will be available in 2023.

Nivolumab

In a 4 to 5 vote, ODAC recommended rescinding the indication for nivolumab for the treatment of patients with HCC and prior sorafenib therapy. There was unanimous agreement from committee members that voting was difficult due to the many factors, including the earlier vote to maintain the indication for pembrolizumab monotherapy. Those in favor of continued accelerated approval for nivolumab in this patient population highlighted the unmet need for second-line options. Rationale against continuing the indication centered on the lack of OS benefit in CheckMate 459 and the inadequacy of the proposed alternative studies to generate satisfactory evidence for efficacy in the second-line setting. Discussion also narrowed in on whether data exist to recommend nivolumab monotherapy over an ipilimumab + nivolumab combination regimen, including debate over whether the group of patients deemed unfit for the dual checkpoint inhibitor combination represent a new indication that was not formally defined nor evaluated in trials to date.

Sponsor Position:

• Nivolumab fills an unmet medical need for the patients who cannot receive bevacizumab in the first-line and whose disease progresses after TKI therapy
• Nivolumab monotherapy is well-tolerated in patients with HCC and associated with fewer toxicities than the ipilimumab-containing combination regimen
• Exploratory analyses in CheckMate 459 favor benefit for healthcare-related quality of life with nivolumab
• Delayed benefit was seen at longer follow-up in CheckMate 459, possibly due to subsequent systemic therapy use in sorafenib arm, including immunotherapy

FDA Position:

• Availability of first-line atezolizumab + bevacizumab (in addition to other second-line options, including combination ipilimumab + nivolumab) has changed the HCC treatment landscape
• Statistically significant OS benefit with nivolumab monotherapy was not shown in the designated confirmatory trial, CheckMate 459
• Alternative confirmatory trials CheckMate 9DX (adjuvant nivolumab) and CheckMate 9DW (first-line ipilimumab + nivolumab) will not provide evidence for benefit with second-line monotherapy
• Data are lacking on efficacy of the monotherapy in the population of patients who cannot tolerate first-line bevacizumab as well as those deemed ineligible for other second-line therapies, such as ipilimumab + nivolumab

Public Comment:

• Nivolumab monotherapy is an important option for many HCC patients, especially given the increased potential for toxicity with ipilimumab-containing combinations
• The safety and adverse event profile of nivolumab is favorable compared to other available second-line therapies for HCC

The FDA is not required to implement the recommendations of ODAC. Committee members also noted that nivolumab is widely available for other FDA-approved indications and that off-label use remains a possibility for the patients with second-line HCC. If the indication were to be ultimately rescinded, expanded access programs and single patient INDs also remain possibilities to allow for continued access.

SITC Meeting Report: April 28 FDA ODAC Summary

The Society for Immunotherapy of Cancer (SITC) is pleased to present this report on the April 28, 2021, meeting of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC).

Anti-PD-L1 atezolizumab was granted accelerated approval for first-line treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma in April 2017, based on an objective response rate (ORR) of 23.5% and median duration of response (DOR) of 59.1 months within cohort 1 of the phase 2 IMvigor210 trial. In May 2017, anti-PD-1 pembrolizumab also received accelerated approval in the first-line setting for metastatic urothelial carcinoma based on an ORR of 28.6% and a median DOR not yet reached (median follow up = 7.8 months) in the phase II KEYNOTE-052 trial. Both atezolizumab and pembrolizumab were initially approved irrespective of tumor PD-L1 status, but the indications were subsequently restricted based on signals for decreased overall survival (OS) with checkpoint inhibitor therapy in the PD-L1-negative populations in interim analyses of the confirmatory trials IMvigor130 and KEYNOTE-361, respectively.

Full approvals for both checkpoint inhibitors were contingent on their respective confirmatory trials, yet statistically and clinically significant OS benefit was not observed in the final analysis of KEYNOTE-361 for pembrolizumab and the interim analysis of IMvigor130 for atezolizumab. The treatment landscape has also evolved in recent years with the full regulatory approval of anti-PD-L1 avelumab as maintenance therapy after completion of standard first-line chemotherapy. However, a significant proportion of patients are not eligible for cisplatin treatment or for any platinum-based regimens, making first-line pembrolizumab or atezolizumab the only options for this otherwise unmet clinical need.

On April 28, 2021, the FDA ODAC panel was asked to vote on the appropriateness of maintaining the accelerated approval for pembrolizumab and atezolizumab for this patient population.

Pembrolizumab

The outcome of the vote at the FDA ODAC meeting was 5 to 3 in favor of maintaining the accelerated approval for pembrolizumab for the first-line treatment of advanced/metastatic urothelial carcinoma in cisplatin-ineligible patients with PD-L1-positive tumors and carboplatin-ineligible patients regardless of PD-L1 status.

Sponsor Position:

• Pembrolizumab fills an unmet need for patients who are ineligible or unwilling to receive platinum-based chemotherapy 
• There was evidence of activity for pembrolizumab from durable responses in long-term follow-up of registration trial as well as demonstrated benefit in KEYNOTE-045 assessing efficacy in the second-line setting
• ORR and favorable safety profiles that were the basis for accelerated approvals for pembrolizumab in KEYNOTE-052 were recapitulated in KEYNOTE-361 
• Crossover from the control arm to subsequent anti-PD-(L)1 therapy in KEYNOTE-361 complicate interpretation of OS and progression-free survival (PFS)

FDA Position: 

• OS and PFS benefit are not validated in confirmatory trials KEYNOTE-361 
• The addition of avelumab as an option has altered the treatment landscape for patients with urothelial carcinoma
• The proposed alternative trial to confirm benefit in metastatic setting (LEAP-011) may not isolate effects of pembrolizumab due to combination with enfortumab vedotin as a comparator
• Studies in peri-operative settings that include cisplatin-eligible patients (KEYNOTE-866 and KEYNOTE-905) will not be complete within a reasonable timeframe

Public Comment: 

• Immunotherapy offers an alternative for many patients who are unable or unwilling to tolerate treatment with platinum-based regimens

Rationale for the vote centered on the significant unmet medical need for ineligible for platinum-based chemotherapy. Although LEAP-011 will only provide single-arm evidence on the efficacy of pembrolizumab monotherapy, the trial was deemed appropriate as a confirmatory study when taken in context of the totality of data from KEYNOTE-052 and KEYNOTE-045.

 

Atezolizumab

ODAC voted 10 to 1 in favor of maintaining the accelerated approval for atezolizumab as first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma who are PD-L1-positive or for platinum-ineligible patients with any PD-L1 status.

Sponsor Positions: 

• Atezolizumab fills an unmet need for patients who are ineligible or unwilling to receive platinum-based chemotherapy 
• Atezolizumab is well-tolerated and displays a favorable safety profile
• Clinically meaningful improvement in ORR and DOR were observed in cisplatin-ineligible patients when compared to historical controls from IMvigor210. Long-term follow up indicates that responses continue to remain durable
• Although the IMvigor211 trial failed to show benefit of atezolizumab in the PD-L1+, previously treated urothelial cancer patients, a signal for increased survival was observed in the ITT population—though this could not be formally assessed for significance due to the pre-specified hierarchical statistical plan           
• Confirmatory trial data from IMvigor130 is not yet mature
• Interim analyses of IMvigor130 suggest a statistically significant PFS benefit in patients receiving atezolizumab + chemotherapy versus chemotherapy alone. Data also trend toward improved OS in the PD-L1+ and ITT populations, though these have not yet been verified via statistical analyses

FDA Position: 

• OS and PFS benefit was not validated in interim analysis of IMvigor130 
• Atezolizumab did not show benefit in the PD-L1-positive group during the second-line setting in IMvigor211, leading to voluntarily withdrawal
• Negative results were also reported with atezolizumab in the adjuvant setting.
• While statistically significant, the 1.9 month improvement in PFS seen in IMvigor130 is not considered clinically meaningful
• Conclusions cannot be drawn from subgroup analyses at this time, due to the prespecified hierarchical statistical design
• Treatment landscape has changed since the 2017 accelerated approval, with demonstrated OS benefit from avelumab maintenance therapy after completing platinum-based chemotherapy 

Public Comment: 

• Immunotherapy offers an alternative for many patients who are unable or unwilling to tolerate treatment with platinum-based regimens

Justification for maintaining the indication predominantly cited the need to wait for final analysis of IMvigor130 to evaluate potential clinical benefit. Of note, data from the arm evaluating atezolizumab + chemotherapy may not only support the full approval of atezolizumab monotherapy, but also influence the regulatory status of an additional indication for the combination regimen. 

A Tribute to Stan Collender: The Budget Guy, Immunotherapy Pioneer (Patient #1), Colleague and Friend (1951-2019)

By Michael B. Atkins, MD

Stan Collender was a man of many remarkable talents. Among his many achievements, he was widely recognized as one of the foremost authorities on the federal budget earning himself the moniker, “The Budget Guy,” and in 2012 receiving both the prestigious Howard Award for lifetime achievement in federal budgeting from the American Society for Public Administration and the James L. Blum Award from the American Association for Budget and Program Analysis. Stan was also my longstanding patient- an immunotherapy pioneer and an advocate whose experience and efforts taught us much about the impact and limitations of immunotherapy. Stan died May 3, 2019. Below is his cancer story from my perspective.

Stan Collender

I first met Stan in 2012 when he presented to my oncology practice status post resection of a Merkel Cell Carcinoma (MCC) on the bridge of his nose. We reviewed his history and the pathology and recommended a wide local excision and a sentinel lymph node biopsy. On hearing this recommendation, he joked that he was a local television celebrity so needed to protect his looks. I assured him that the plastic surgeon was up to the challenge.

After the successful surgery, we followed Stan at regular intervals. About 1 year later we noted he had developed an enlarged neck lymph node. Upon hearing this news Stan became diaphoretic, pale and promptly fainted. While he was out cold lying on an exam table and then gradually regaining consciousness, I remember thinking, “this is not going to be easy.”  But I never anticipated the novel, groundbreaking twists and turns Stan’s case would take, nor the heroic role he would assume as a patient advocate, or that I would be writing this posthumous tribute to a man I came to admire and care deeply about as a courageous colleague and friend.

Despite Stan’s tremulous start, he was an absolute rock thereafter. He underwent lymph node dissection and post-operative radiation therapy without a hitch. He subsequently developed a solitary brain lesion, which was also resected and treated with adjuvant stereotactic radiation to the resection bed. Unfortunately he developed widespread systemic disease six months later. In weighing treatment options available at the time, I recommended he participate in a clinical trial involving a then experimental immunotherapy, pembrolizumab, that we’d had good experience with in patients with melanoma, but had yet to test in patients with MCC. He volunteered for the clinical trial without hesitation, despite it being conducted in Seattle. He was literally Patient # 1 - a pioneer- on this important Cancer Immunotherapy Network (CITN) trial led by Drs. Paul Nghiem and Shailender Bhatia. Every 3 weeks he flew from DC to Seattle to receive his experimental treatment.  The pembrolizumab worked well: after two years of treatment his disease there was no visible signs of residual disease on imaging studies- his disease was apparently gone.  Not only did this treatment help Stan, but based on the results of this groundbreaking clinical trial, pembrolizumab receive FDA approval and is now the standard of care for patients with treatment naïve advanced MCC, providing benefit to countless patients with this disease.

Stan embraced this treatment success and his new lease on life with his typical gusto. He wrote an OpEd in the New York Times where he described his clinical trial experience. Rejecting the concept of being a guinea pig, he wrote he felt more like Chuck Yeager breaking the sound barrier and going where no one else had gone before. He encouraged others to participate in clinical trials and became a leading spokesman and a tireless advocate for the immunotherapy, MCC and cancer clinical trials communities. Just like Chuck Yeager in aviation, in MCC and immunotherapy circles, he became a national hero.

With his cancer in remission, Stan and I moved beyond our traditional patient-physician relationship: we became collaborators and friends. When Stan joined the Georgetown faculty, teaching public relations and public policy classes, we officially became colleagues.  Over lunches we strategized on how we could best represent the value of immunotherapy relative to other cancer treatments, as well as how to encourage cancer clinical trials participation and more public private partnerships such as the CITN trial he’d participated in.

Stan was frequently in attendance when I gave educational briefings to Congressional staffers, and welcomed me singling him out as Patient #1 on the MCC CITN trial. We served together on SITC committees focusing on measuring the value of immunotherapy, where Stan’s personal experience and budget expertise were both unique and invaluable. When I received my endowed chair, I was honored to have Stan and his beloved wife Maura, join me at the dinner ceremony and celebration.

In 2017, Stan was invited to give the Keynote lecture at the annual American Association of Cancer Institute’s meeting in DC. He talked about his views of the upcoming federal budget and its potential impact on cancer research funding, but he also described his personal battle with cancer, his experience as a survivor, and thanked me publicly for having encouraged him to pursue the CITN trial. Sitting in the audience, I felt both like a proud teacher witnessing my prized pupil excel, and grateful to see him healthy and choosing to apply his experience, talent and renewed health to benefit others.

Over lunches, we talked about his potentially running for Congress in the Virginia 6^th in 2018 and how wonderful it would be to have a vocal cancer survivor and immunotherapy and clinical research advocate in Congress. He ultimately withdrew this pursuit, but came to my house for a gathering of concerned voters in his ex-candidate’s capacity to discuss the race and promote the candidacy of Jennifer Wexton - who ultimately was elected to serve the district.

And so it went. Stan and I had developed a shared mission and fought together on several fronts for its success. I thought we’d be doing this together for the rest of our careers.

Then all hell broke loose. Stan was almost 2 years out from his last therapy, a time when we usually consider patients who have responded to immunotherapy to be cured. So it was a shock when he presented in December 2018 with hand weakness, headaches and difficulty swallowing and a head MRI which showed that his lateral ventricles were packed with tumor. I had never seen anything like this presentation before and had no idea that MCC could do this. His tumor had recurred exclusively in one of the few places where the immune system doesn’t reach.

The word spread like wildfire through the MCC and immunotherapy communities. It was devastating. The pioneer/ hero- MCC patient # 1 - had relapsed. I was once again thrust into action as his physician, proposing a variety of approaches all focused on trying to get his immune system re-activated and into his ventricles where the tumor was hiding. A lot of my proposed treatments were quite involved and associated with considerable risk, but Stan was always positive. He would respond to my carefully chosen words of encouragement such as,  “I hope this works” or “This could work” with an optimistic “It is going to work” and a courageous “Let’s do it!”  Although Maura was more attuned to the uncertainty in my recommendations, Stan’s optimism usually prevailed.

Ultimately, the tumor could not be controlled and we ran out of both treatment options and optimism. Maura and Stan decided to focus on comfort measures. Stan passed away peacefully at home on May 3^rd, 2019.

At his memorial celebration a few weeks later, person after person spoke about how they knew Stan, each describing a unique contribution he had made during his remarkable careers in Government, public policy, public relations, as well as in intramural football and as a family man. Clearly Stan was a true “mensch” with his many interests, passions and strong commitment to both his family and the world around him. His impact on the MCC, immunotherapy and cancer clinical trials communities was profound and enduring. Even in death, Stan remains a teacher and an advocate: his cancer taught us about potential new obstacles to effective immune therapy and like Chuck Yeager, his legacy as “Patient Number 1” will undoubtedly inspire research efforts to overcome them. I will miss this remarkable man- rest in peace my friend.

JITC Letter from the Editor - August 2019

Dear JITC Readers,

In the August edition of the JITC Digest, I would like to highlight the following articles. First, “The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC),” by Ezra E.W. Cohen et al. details the first new FDA approvals for patients with squamous cell carcinoma of the head and neck (HNSCC) since 2006, including the most recent 2019 approval of pembrolizumab as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC in combination with chemotherapy for all patients or as monotherapy for patients with HNSCC whose tumors express PD-L1. These consensus guidelines serve as a foundation to assist clinicians’ understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit.

Furthermore, the article, “T cells expressing NKG2D chimeric antigen receptors efficiently eliminate glioblastoma and cancer stem cells” by Dong Yang et al. confirms the high expression of NKG2DLs in human glioblastoma cell lines, CSCs, and tumor samples and provides evidence that NKG2D CAR T cells effectively target glioblastoma cells and CSCs in an NKG2D-dependent manner, thus reporting on an encouraging therapeutic approach for glioblastoma patients.

Next, the research article entitled “Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2–IL-6 cascade,” by Yong-Qiang Chen et al. reveals novel cellular and molecular mechanisms of tumor-derived extracellular vesicles in regulating CD4+ effector T cell function and pinpoints tumor cell-released autophagosomes (TRAPs) as a therapeutic target for cancer immunotherapy, specifically reporting HSP90-alpha on the surface of TRAPs as a novel target.

“Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments,” by Shreya Raghavan et al. details the hanging drop spheroid model developed to investigate pro-tumoral macrophage activation in response to CSCs and the role of WNT pathways in CSC-macrophage interactions. Such insight could provide new targets for reducing CSC-burden in ovarian cancer.

“HERA-GITRL activates T cells and promotes anti-tumor efficacy independent of Fc-gamma-R-binding functionality,” by David M. Richards et al. describes the development of a novel agonistic HERA molecule targeting GITR for which the underlying HERA-GITRL structure overcomes significant limitations of bivalent antibody-based approaches by mimicking the natural trimeric ligand, and thus inducing optimal trimeric assembly of the GITR receptors.

Finally, the clinical study, “First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors,” by Kohei Shitara et al. reports on single agent IT1208, a humanized anti-CD4 immunoglobulin G1 mAb, which is shown to successfully deplete CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, warranting further investigations, possibly in combination with immune checkpoint inhibitors.

With best regards,

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

To view the entire August 2019 JITC Digest, please click here. 

Why combine immunotherapy with targeted radiation therapy?

by Christian Hyde, MD

In the World War 2 movie, "Saving Private Ryan," a small town held by Allied foot soldiers is being over-run by Nazi tanks. At the crucial moment in the battle, when all hope seems lost, a friendly Allied airplane turns the tide by bombing an armored tank and rallying the exhausted defenders.

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.

President's Message - December 2017

Dear Colleagues,

The past year has been one of significant scientific progress for the field of cancer immunotherapy and tumor immunology. Among the highlights:

• Pembrolizumab received U.S. Food and Drug Administration (FDA) approval for treating patients with MSI-H/dMMR-positive solid tumors, marking the first ever “tissue-agnostic” designation for any cancer therapeutic, defining disease based on biomarker status rather than tissue location
• CAR T cell therapies obtained initial FDA approvals for treating both DLBCL and B-ALL following very positive clinical trial results
• Cancer immunotherapies also continued to gain new indications by obtaining initial FDA approvals in hepatocellular carcinoma (nivolumab), Merkel Cell Carcinoma (avelumab), and gastric/GEJ cancers (pembrolizumab)
• Multiple cancer immunotherapeutics including nivolumab, pembrolizumab, durvalumab, avelumab, and atezolizumab became options for treating patients with bladder cancer

As we look ahead to 2018, the Society for Immunotherapy of Cancer (SITC) will continue to create opportunities for collaboration and scientific exchange for our growing membership base and beyond. Today, I’d like to single out two inter-connected workshops SITC has planned for May 2018 on biomarkers and cancer immune responsiveness.

Ten years after its inception, the SITC Immune Biomarkers Task Force will lead a two-day workshop to discuss critical next steps in biomarker science and assay development. Session topics will include best practices and validation; biomarker identification; data and specimen sharing and much more.

SITC’s newly-formed Cancer Immune Responsiveness Task Force will host a two-day workshop on topics that include tumor evolution in the immune competent host and the resulting immune landscape; identification of common pathways that should be targeted to understand and increase immunogenicity among silent or “cold” cancers and more.

The Annual Meeting & Pre-Conference Programs – which will take place at the Walter E. Washington Convention Center, Washington, D.C. in 2018 due to continued growth and excitement – will always be our society’s hallmark event. SITC hosts interim programs throughout the year to provide focused opportunities to move new developments and initiatives forward for improving cancer patient outcomes through the advancement of science and clinical application of cancer immunotherapy.

Both of the workshops mentioned will be open to the public. Stay tuned to SITC in the New Year for additional event information, including dates and location.

Sincerely,

Lisa H. Butterfield, PhD

SITC President

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.

On Tap at SITC 2017 - Nov. 10

On Tap Today

The wait is over! The 32nd Annual Meeting (SITC 2017) kicks off this morning. On-site registration and badge pickup opens at 7 a.m. for those who are joining us for the first time this week, with a breakfast also available before sessions begin at 8 a.m.

SITC 2017 is the first Annual Meeting for Lisa H. Butterfield, PhD, as President of the society. Dr. Butterfield had served as Vice President of SITC the past two years before becoming the first female President of SITC in its history following last year's Annual Meeting.