The Sentinel

THE OFFICIAL BLOG OF THE SOCIETY FOR IMMUNOTHERAPY OF CANCER (SITC).

Wednesday, December 16, 2020

Letter From the Editor- December


Dear JITC Readers,

Welcome to the final JITC digest of 2020. You are likely reading this email within a few days of the winter solstice—the shortest day of the year. Although 2020 has been a highly challenging year with some dark and difficult times, it is reassuring to know that each passing day will come with a little more light. 
 
Although the term has by now become cliché, we are indeed living in unprecedented times. Yet looking back upon 2020, some bright spots emerge from the dark and challenging circumstances in which we have been living. The society’s various task forces and working groups published several impactful papers, one of which, by Brian Gastman and colleagues on the SITC Surgery Committee, appears in this month’s issue. SITC also successfully carried out its first ever all-virtual annual meeting, and it was an amazing opportunity to reconnect with colleagues from all over and experience the very best in immunotherapy research (even if our interactions were through videochat windows). 
 
Additionally, JITC increased its impact factor to 10.252 in 2020, making it the highest ranked fully open access immunology journal and in the top 7 percent of all journals published in the oncology and immunology categories. I’m so grateful to you, our JITC readers, for your constant support of the journal, as well as the tireless efforts of all of our editors and peer reviewers. Thank you all so much for helping to make JITC the field-leading journal that it is today.
 
The articles in this month’s JITC digest are exemplary of why the journal continues on an upwards trajectory of success. Not only are the highlighted studies well-designed and tightly controlled, but the results forecast important trends for the future of the immunotherapy field. 
 
Two unique angles on therapeutic vaccination are provided by Juliane Schuhmacher et al and Iuliia Efimova et al, demonstrating that synthetic long peptides and cells dying an iron-dependent death, respectively, may offer advantages for the development of anti-tumor immunity. 
 
Combination regimens including multi-tyrosine kinase inhibitors and checkpoint blockade are the subject of reports by Javier Martin-Broto et al and Kohei Shigeta et al, further establishing the importance of angiogenesis in immune exclusion and demonstrating that combination strategies could expand the number of tumor types susceptible to PD-(L)1-targeting therapies. 
 
Finally, Diana Canals Hernaez and colleagues provide proof of concept that antibodies specific to tumor-restricted glycans can be developed and that they can specifically kill cancer cells when conjugated to toxic payloads.
 
I hope you enjoy this month’s JITC digest, and I wish a sincere and heartfelt happy holidays and best wishes for the New Year!
 
Best,

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

To view the entire September 2020 JITC Digest, please click here

Thursday, December 10, 2020

President's Message - December 2020

 Dear Colleagues,

I would like to open this month’s message, my last as SITC President, with a warm thank you to all of the attendees, supporters, organizers, faculty, staff and other volunteers who helped make our society’s 35th Anniversary Annual Meeting & Pre-Conference Programs (SITC 2020) a record breaking success. More than 5,200 professionals in the cancer research community gathered virtually from Nov. 9–14 to present and hear the latest data in the lab and advances achieved in the clinic in immunotherapy. 

While we were unable to share and celebrate the latest advances in our field in person – more individuals attended SITC 2020 than any other society program in our history. A fitting milestone as we marked 35 years of SITC contributions in immunotherapy and tumor immunology.

To mark our 35th anniversary, SITC honored more awardees than ever before during its Annual Meeting, This year, SITC presented its Lifetime Achievement Award, a new honor for the society, to Tara Withington, CAE. For more than 20 years as SITC’s Executive Director, Tara has devoted all of herself to help fulfill our society’s mission and achieve new heights. Her vision helped SITC launch countless integral SITC initiatives including the connectED online education platform, the SITC Sparkathon, the certificate in cancer immunotherapy program, Advances in Cancer Immunotherapy™ regional education programs and many others.

Congratulations to all of the SITC 2020 Award recipients. Click here for a complete listing of those honored, including the dozens of young investigators who received awards this fall. And don’t forget, for all those who registered for SITC 2020, you can access program presentations through the end of the year via on-demand video in the SITC 2020 virtual platform.

The virtual meeting allowed SITC to expand our Annual Meeting programming to a truly global audience. This past year, SITC’s membership base grew to represent more than 60 countries around the world. Increasing global access to immunotherapy is one of the society’s key strategic priorities. One way we are seeking to achieve this goal will be through this month’s virtual workshop, Global Access to Cancer Immunotherapy: Closing the Gaps. Organized through the guidance and strategic vision of the SITC Global Access and Impact Committee, which is chaired by David Kaufman, MD, PhD, this workshop will offer leaders an opportunity to discuss and define minimal infrastructure requirements for safe and effective IO administration across the globe. Congruent with SITC’s mission to ensure that all immunotherapy advancements are freely available, materials from this workshop will be available on SITC Cancer Immunotherapy connectED after the conclusion of the workshop. We invite you to view the materials later in December and participate in future discussions concerning international IO accessibility.

Have you completed your holiday shopping? As we close out 2020, I ask that you consider including the Forward Fund in your year-end giving.  Making a donation to SITC’s Forward Fund, supports the future of the field through grants and awards for young investigators.  You can make the gift in honor or in memory of a loved one and help advance the Society’s mission.  They’ll receive a card notifying them of your generous gift and you’ll receive a gift recipient for tax purposes.  You can also purchase a CheckPoints T-shirt or Mask as a truly unique gift for someone you care about. If you missed the CheckPoints at SITC 2020, you can watch their happy hour performances here.  Further, if you are completing some holiday shopping on Amazon, use SITC’s Amazon Smile hyperlink, which triggers a 0.5 percent donation from the online retailer to our society on eligible purchases. We appreciate your kindness as we close out the calendar year.

As we approach the final days of 2020, I’m pleased to pass the baton of SITC leadership to fellow colleague and friend Patrick Hwu, MD. I look forward to seeing and supporting Dr. Hwu’s tenure as SITC President as he helps make the next two years for SITC our best yet.

Happy holidays to the entire SITC family.

Sincerely,









Mario Sznol, MD

SITC President

Wednesday, November 18, 2020

JITC Letter From the Editor- November 2020


Dear JITC Readers,

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. 

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

Saturday, November 14, 2020

SITC 2020 Scientific Highlights – Nov. 14, 2020

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 14, 2020, sessions of the 35th Anniversary Annual Meeting.

Method for personalized immunotherapy response prediction developed

Plasma-based proteomic profiling as a tool for predicting response to immunotherapy in melanoma patients

Michal Harel, PhD (Oncohost LTD), discussed a method for profiling patients with melanoma to predict response to immunotherapy. The group utilized proteomic profiling of plasma samples before treatment and early after initiation of anti-PD-(L)1 therapy to develop a predictive signature using machine learning. They also aimed to identify biological pathways that differed between responders and non-responders.

A 3-protein signature was developed and was able to distinguish responders from non-responders in the validation cohort with a sensitivity and specificity of 0.75 and 0.9, respectively. Using the signature, a personalized response prediction could be developed for individual patients. Further evaluation of biological pathways identified potential resistance mechanisms in non-responders, such as upregulation of inflammation, proliferation, metastasis and angiogenesis processes. Different pathways were upregulated in tumors that failed to respond to PD-(L)1 monotherapy compared to those also treated with anti-CTLA-4, indicating varying biological underpinnings for resistance. In a case study, the group discussed identification of a potential resistance-associated protein in a patient with melanoma, leading to recommendations for potential clinical trials targeting that resistance mechanism.

CD47 blockade may boost immune response to TNBC

An immune-competent tumor organoid platform to test novel immune checkpoint combinations targeting the receptor CD47 in triple negative breast cancer

Elizabeth Stirling, MS (Wake Forest School of Medicine), presented preclinical methods to investigate CD47-targeted therapies in triple negative breast cancer. The group utilized organoid tissue culture, murine models, and tissue analysis in their study. 

CD47 expression varied between primary and metastatic human TNBC tumors and was also higher in non-responding tumors than responders to PD-1 therapy. Given this, the group investigated CD47 blockade in murine models of TNBC and found that this therapy significantly decreased tumor growth. There was evidence for increased intratumoral CD8+ T cells and granzyme B expression in the tumor tissue after treatment. Treated tumors were also more sensitive to PD-L1 blockade. A 3D organoid model, which included co-incubation of tumor-specific cytotoxic T cells, was used to test CD47 therapy as well, and also revealed increased granzyme B and interferon gamma expression with treatment. The authors feel that the organoid model used in this study could be a valuable resource for future therapeutic studies.

p53-specific T cell therapy may be efficacious and widely-applicable

Adoptive T cell therapy targeting somatic p53 mutations

A p53-targeted adoptive T cell therapy was discussed by Peter Kim, PhD (National Cancer Institute). Given that p53 is the most commonly-mutated cancer driver gene, cell therapies targeting common p53 mutations may be widely-applicable.

The group found that 22% of screened patient TILs were responsive to mutant p53, which included 46 different TCRs. However, patients that were treated with autologous TILs largely did not respond to the therapy, with 2 PRs found in 12 patients. The infused TILs were found to have low frequencies of mutant p53-specific TILs, and had a high level of differentiation and exhaustion. The group hypothesized that genetic engineering of T cells may overcome these problems and thus treated a patient with breast cancer with adoptive transfer of autologous PBLs that had been retrovirally transduced with an anti-p53 R175H TCR. The patient’s tumors shrunk by 55% after this treatment, despite having progressed on 10 other therapies. The engineered cells were found to be more persistent and have greater p53 reactivity than naturally-occurring TIL, making this strategy a promising one for future wide-scale immunotherapy.

Friday, November 13, 2020

SITC 2020 Scientific Highlights – Nov. 13, 2020

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 13, 2020, sessions of the 35th Anniversary Annual Meeting.

Combination ICI shows benefit for angiosarcoma

A multicenter phase II trial (SWOG S1609, Cohort 51) of Ipilimumab and Nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART)

Michael Wagner, MD (University of Washington), presented the results from cohort 51 of the SWOG S1609 DART trial, which investigated combination nivolumab and ipilimumab in patients with angiosarcoma. Sixteen patients were enrolled in this cohort with the primary endpoint of response rate.

The overall response rate was 25%, which included partial responses in three patients with cutaneous disease of the scalp/face and one patient with radiation-associated breast angiosarcoma. Six-month progression free survival was estimated at 38% across all patients. Molecular tumor characterization was performed in eight patients and revealed at least two deleterious genomic alterations in each patient, though these were unique to each individual. Responders in this cohort tended to have intermediate to high tumor TMB, though data was only available for two responders. Adverse event profiles were as expected. Given the encouraging results in this aggressive cancer, future study is anticipated.

Triplet therapy may benefit pancreatic cancer

Urelumab (anti-CD137 agonist) in combination with vaccine and nivolumab treatments is safe and associated with pathologic response as neoadjuvant and adjuvant therapy for resectable pancreatic cancer

Lei Zheng, MD, PhD (Johns Hopkins University School of Medicine), and colleagues investigated the treatment of pancreatic cancer with combination urelumab, nivolumab and a vaccine, GVAX. Preclinical and early clinical studies by the investigators indicated that adding the anti-CD137 antibody urelumab to the other two therapies could be synergistic, initiating this study. Ten patients without previous treatment were enrolled.

Patients received one dose of each therapy, followed by R0 resection two weeks later. Following surgery, patients were treated with additional immunotherapy cycles in addition to standard-of-care chemotherapy. No patients had to delay surgery due to toxicities, and three patients exhibited moderate pathologic responses at the time of surgery, which was not anticipated. Nine of the ten patients remain disease-free at a median follow-up of one year. No notable safety signals were seen, with the most common toxicity being nausea. A trend toward an increase in activated T cells (evidenced by granzyme B expression) was noted after the combination treatment, along with expansion of T cell clones expressing granzyme B and PD-1.

Antibody targeting p53 peptide complex shows therapeutic promise

Targeting a shared TP53 neoantigen with bispecific T cell retargeting antibody

Emily Hsiue, MD (Johns Hopkins University School of Medicine), discussed a T cell retargeting antibody, known as H2, which recognizes CD3 on T cells and a mutant peptide presented by HLA resulting from p53 mutations. As TP53 is the most commonly-mutated cancer driver gene, the group anticipated that a therapy targeting a shared neoantigen resulting from these mutations would be widely-applicable.

Using a phage display library, an scFv was identified that specifically binds p53 R175H/HLA-A*02:01. Linking this neoantigen-specific scFV with an anti-CD3 scFv generated the H2 MANAbody (mutation-associated neoantigen), which was tested in vitro and in vivo. Cellular studies verified that the agent was able to induce cytotoxicity against cancer cells expressing the mutant peptide but not the wild-type, including cells that were engineered to express the antigen and those at endogenous levels. Murine studies using xenograft tumors also demonstrated therapeutic efficacy. The authors hypothesize that their approach of targeting HLA-bound peptides may increase the pool of potentially actionable therapeutic targets.

Radiotherapy, anti-CTLA-4 and CD40 agonism may synergize

Radiotherapy and CTLA-4 blockade expand anti-tumor T cells differentiation states and cooperate with CD40 agonist to induce tumor rejection

The mechanisms behind the combination of radiotherapy and anti-CTLA-4 treatment were investigated by Nils Rudqvist, PhD (Weill Cornell Medicine/MD Anderson Cancer Center), and colleagues. The group employed the murine 4T1 model to dissect the T cell response to these therapies and other combinations in order to determine potential synergistic therapies.

The combination of radiotherapy and anti-CTLA-4 therapy induced clonal expansion and tumor infiltration of T cells in these preclinical models, increasing both these measures over either therapy alone. Each individual therapy impacted different T cell compartments. Radiotherapy boosted effector T cell populations, increasing CD8+Gzmb+Lag3+Pd1+ cells, while CTLA-4 monotherapy boosted Th1 cells, expressing CD4, CD40lg and IFNg. The combination had the most impact on CD8+TNF+Ifng+ polyfunctional cells. The group tested additional therapeutic combinations based on these T cell population results, including the addition of antibodies targeting PD-1, LAG-3, and CD40. The addition of a CD40 agonistic antibody to the radiotherapy and CTLA-4 combination resulted in increased therapeutic efficacy and better tumor control, while the other two additions had no effect. This triplet combination may represent a future avenue for improving immunotherapy effectiveness in patients.

B cell vaccination may boost immune response to glioblastoma

B-cell-based vaccination elicit potent immunity against glioblastoma

A B-cell-based vaccination therapy for glioblastoma was discussed by Catalina Lee-Chang, PhD (Northwestern University). This therapy, known as Bvax, was developed by activating 4-1BBL+ B cells in vitro using CD40 and IFNgamma receptor ligation, in addition to incubation with tumor cell lysate. These activated B cells could then be intravenously administered to mice bearing glioblastoma tumors or tested in vitro for their effects on tumor cells.

In vitro studies indicated improved tumor cell killing by T cells with co-incubation of Bvax in a concentration-dependent manner. Enhanced CD8+ T cell activation and infiltration into the tumor-bearing brain was observed after co-administration of Bvax and tumor-specific T cells in mouse models. Bvax also primarily produced IgG antibodies in vivo, which were tumor-reactive. Administration of these Bvax-derived IgG to tumor-bearing mice was able to extend their survival. A combination therapy of radiotherapy, Bvax, CD8+ T cells, and anti-PD-L1 was able to significantly extend the survival of tumor-bearing mice as well, also increasing T cell infiltration in the brain. The role of B cells is thus important to explore in order to improve the responsiveness of “cold” tumors to immunotherapy.

Combination PI3K-g and PD-1 inhibition benefits ICI-experienced patients with SCCHN

Updated clinical data from the squamous cell carcinoma of the head and neck (SCCHN) expansion cohort of an ongoing Ph1/1b Study of eganelisib (formerly IPI-549) in combination with nivolumab

Ezra Cohen, MD (University of California, San Diego), presented findings from the phase 1/1b study, MARIO-1, investigating the combination of eganelisib and nivolumab in patients with squamous cell carcinoma of the head and neck that progressed on prior PD-(L)1 therapy. Patients received eganelisib, a PI3K-g inhibitor, at 40 mg QD PO and nivolumab 240 mg Q2W. Twenty-one patients with head and neck cancer were included in this analysis.

The safety profile of the combination was largely as expected, with the most common treatment-related adverse events including fatigue, nausea, pyrexia and pruritis. The overall response rate in patients with tumors that had progressed on immediate prior PD-(L)1 therapy (n=20) was 10%, with both of the partial responses occurring in patients with 1-2 prior lines of therapy. For patients with 3+ prior therapies, no responses were noted, though 5/10 patients did experience stable disease. Median PFS in the whole population was 17 weeks. Higher benefit was noted in patients with HPV+ tumors, as 50% of these achieved stable disease, while none of the HPV- tumors did. The investigators are beginning a window-of-opportunity study in HNSCC based on the findings in this trial.

Thursday, November 12, 2020

SITC 2020 Scientific Highlights – Nov. 12, 2020

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 12, 2020, sessions of the 35th Anniversary Annual Meeting.

Investigations of oncolytic viruses in glioblastoma reveal immunological differences

Comparison of Two oHSV Vectors for the Treatment of Glioblastoma

Joseph Jackson, PhD (University of Pittsburgh), and colleagues compared two oncolytic herpes simplex virus vectors for their efficacy in treating preclinical glioblastoma. The two strains included an HSV-1 KOS strain called KG4:T124 and an F strain derivative called rQNestin34.5v.1, and were tested in the murine syngeneic GL261N4 and CT2A models and in vitro assays.

In vitro tests revealed that both viruses entered cells with similar efficiency, but that rQNestin34.5v.1 was able to induce greater viral-mediated cytotoxicity due to a higher replication rate. Analysis in the GL261N4 model showed that rQNestin34.5v.1 also increased animal survival through reduced tumor burden, but increased efficacy was not noted with repeated injections of this virus. However, multiple injections of KG4:T124 did improve the efficacy of this virus in the GL261N4 orthotopic model through increased survival. Neither virus was able to control the more aggressive CT2A tumors. Increased tumor infiltration of tumor-associated macrophages and polymorphonuclear cells was seen after treatment with each virus, but an increase in beneficial anti-tumor immune cells, like NK or T cells, was not noted. Ongoing preclinical investigations like this one may help to elucidate the mechanisms of response and resistance to immunotherapies in difficult-to-treat glioblastoma.

Immune checkpoint inhibition may be effective for certain leptomeningeal metastases

Pembrolizumab for Patients with Leptomeningeal Metastasis from Solid Tumors: Efficacy, Safety and Cerebrospinal Fluid Biomarkers

An investigation of pembrolizumab for the treatment of leptomeningeal metastases was presented by Jarushka Naidoo, MB, BCH, MHS (Johns Hopkins Sidney Kimmel Cancer Center). Thirteen patients with leptomeningeal metastases from solid tumors, including HR+ breast cancer, glioma, NSCLC, head and neck carcinoma, and cutaneous squamous cell carcinoma, were treated on the trial and followed for the primary endpoint of CNS response after 4 cycles.

A CNS response was recorded in 38% of patients on the trial, which included durable complete responses in a patient with cutaneous squamous cell carcinoma (OS: 3+ years) and another with MET-exon14+ NSCLC (OS: 9 months). One patient experienced a partial response and two patients displayed stable disease in the CNS. Overall, the median PFS in the CNS was 2.9 months and the median OS was 4.9 months. A cytokine analysis indicated that there were differences between responders and non-responders, such as reduction in levels of certain pro-inflammatory cytokines in responders. The investigators also determined that detection of tumor DNA in the CSF may be a better method for detecting leptomeningeal metastases than the currently-used technique of CSF cytology. This study indicates that immune checkpoint inhibition may be a tool for managing leptomeningeal metastases from certain cancers.

Extracellular vesicle PD-L1 may predict response to ICIs in NSCLC

Dynamic change of PD-L1 expression on extracellular vesicles predicts response to immune-checkpoint inhibitors in non-small cell lung cancer patients

Diego de Miguel Perez, PhD, MSc (University of Maryland), discussed a study of extracellular vesicles as biomarkers in patients with NSCLC. Patients in the trial were receiving immune checkpoint inhibitors for advanced/metastatic NSCLC and had tissue samples collected at baseline and plasma samples (to evaluate extracellular vesicles) collected at baseline and at first response evaluation eight weeks later.

Contrary to some other studies, tissue PD-L1 expression did not correlate with treatment response in this cohort, nor was it correlated with baseline PD-L1 levels on extracellular vesicles (EVs). A trend was observed in the dynamics of PD-L1 expression on extracellular vesicles, however, as patients who did not respond to checkpoint inhibition tended to have PD-L1 levels increase on EVs throughout treatment. Similarly, patients with a response to therapy showed stable or decreasing levels of PD-L1 on EVs, as measured by immunoblot. The increase in PD-L1 on EVs was thus significantly associated with shorter overall survival (HR: 4.34, p=0.037) and shorter progression-free survival (HR: 5.06, p=0.025). EVs should be evaluated in larger cohorts of patients to validate their use as a non-invasive biomarker.

Novel agent may control ICI colitis without impacting cancer treatment efficacy

Preclinical development of a novel colon-targeted therapeutic for the treatment of Immune Checkpoint Inhibitor (ICI)-colitis

Nazli Dizman, MD (Yale New Haven Hospital), presented a preclinical investigation of a novel colon-targeted immunosuppressive agent for the management of immunotherapy-induced colitis. The agent, VV2003, is a selective CRAC inhibitor that is administered orally and has low epithelial permeability in the gut to limit systemic absorption and effects, like inhibiting responses to immunotherapy.

Pharmacokinetic studies in mice verified low plasma exposure of VV2003 and high levels in the colon regardless of inflammation status. The agent was also tested in murine models of colitis, showing improvements in colitis markers like histology scores, colon myeloperoxidase, and endoscopy scores over treatment with a vehicle. Importantly, treatment of mice with VV2003 did not appear to impact the efficacy of immune checkpoint inhibition on tumor growth. An ongoing study is investigating the impact of VV2003 on colon samples from patients with suspected immune-related colitis. With two patients to date, there appears to be a reduction in MCP-1 after treatment, though future studies are needed to confirm the influence of VV2003 in human patients, including a planned phase 1a/b trial.

DLL3 bispecific T cell engager may be effective for SCLC management

AMG 757, a half-life extended bispecific T-cell engager (BiTE®) immune therapy against DLL3 in SCLC: phase 1 interim results

A phase 1 trial of AMG 757, a T cell engager against DLL3, in small cell lung cancer was discussed by Hossein Borghaei, DO, MS (Fox Chase Cancer Center). The agent combines anti-CD3 and anti-DLL3 domains with an Fc region to increase circulation half-life. This study, as the first-in-human investigation, followed a dose exploration/expansion format with target doses from 0.003 to 10 mg. Forty patients were enrolled, all of whom had received at least one prior systemic therapy for SCLC.

Treatment-related adverse events of any grade were noted in 80% of patients, with 18% being grade 3+. The most common any-grade event was cytokine release syndrome, though these were all of grade 1-2 and most common with the first dose of AMG 757. There was one instance of grade 5 pneumonitis. Across all dose levels, confirmed partial responses were noted in 16% of patients, all at doses of at least 0.3 mg. the four-week disease control rate in the study was 45%. Responses are ongoing in 5/6 patients with a median follow up of 8.8 months. Investigation of this agent, including determining the optimal monotherapy dose, is still ongoing.

Wednesday, November 11, 2020

SITC 2020 Scientific Highlights – Nov. 11, 2020

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 11, 2020, sessions of the 35th Anniversary Annual Meeting.

AXL and PD-1 inhibition may benefit select patients with non-small cell lung cancer

A PhII study of bemcentinib, a first-in-class selective AXL kinase inhibitor, in combination with pembrolizumab in pts with previously-treated advanced NSCLC: Updated clinical & translational analysis

James Spicer, PhD FRCP (King’s College London), discussed the BGBC008 trial, investigating the combination of the AXL inhibitor bemcentinib with pembrolizumab for non-small cell lung cancer. Results were presented for the cohort of patients who had progressed on prior immunotherapy with the primary endpoint of overall response rate.

Sixteen patients were included in this analysis, all of whom had been treated with an immune checkpoint inhibitor as their most recent therapy. Biomarker status was available for 13 patients: 8 were cAXL-positive while 5 were negative, and 5 patients had PD-L1 TPS >=50%, 5 had TPS of 1-49%, and 3 had TPS <1%. Responses to the combination therapy were only observed in patients with cAXL positivity (combined tumor and immune cell expression), as 1 partial response and 5 stable disease results were recorded in these seven patients. Median PFS for AXL-positive patients was 4.73 months compared to 1.87 months for cAXL-negative. Common treatment-emergent adverse events included liver enzyme elevations and diarrhea. The authors proposed that AXL may promote T cell dysfunction and exhaustion, among other mechanisms, and blocking this function could potentiate immune checkpoint blockade therapy, even in these patients who progressed on prior immunotherapy.

Combination of bempegaldesleukin and nivolumab results in long PFS in melanoma

Progression-free survival and biomarker correlates of response with BEMPEG plus NIVO in previously untreated patients with metastatic melanoma: results from the PIVOT-02 study

Updated results from the PIVOT-02 study, investigating the combination of nivolumab and the IL-2 pathway agonist bempegaldesleukin, were presented by Adi Diab, MD (MD Anderson Cancer Center). Patients (n=41) were eligible for the trial if they had previously untreated metastatic melanoma and were evaluated for the primary endpoints of overall response rate and safety.

The median follow-up for this report was 29.0 months. At this time, the ORR was 53%, including a complete response rate of 34%. The median time to response was 2.0 months, and to complete response was 7.9 months. The median PFS was 30.9 months, and the median overall survival was not reached. The 36-month OS rate was 70.9%. Biomarker studies revealed signatures that correlated with response, including the interferon-gamma gene expression profile and CD8+ TILs in baseline samples. Dynamic changes in the peripheral blood were also observed after the first dose of treatment, resulting in increases in the polyfunctional strength index of CD4+ and CD8+ T cells, and in the level of circulating eosinophils. The encouraging findings in this phase 2 trial have led to the initiation of a phase 3 trial of the same combination.

Neoadjuvant oncolytic virus therapy may benefit patients with melanoma

3-year results of the phase 2 randomized trial for talimogene laherparepvec (T-VEC) neoadjuvant treatment plus surgery vs surgery in patients with resectable stage IIIB-IVM1a melanoma

Reinhard Drummer, MD (University Hospital of Zurich), and colleagues studied the use of talimogene laherparepvec (T-VEC) as a neoadjuvant treatment for patients with resectable melanoma in a phase 2 trial. This presentation provided an interim analysis of the impact of neoadjuvant T-VEC compared to surgery alone with a median follow up of 41.3 months.

The primary analysis of recurrence-free survival indicated improved outcomes with neoadjuvant T-VEC, as these patients experienced 3-year RFS rates of 46.5% compared to 31.0% with surgery alone by Kaplan-Meier estimates. Removing potential effects of subsequent therapies increased the difference between the two arms, with estimated 3-year RFS of 49.1% with T-VEC and 22.9% without. Overall survival was also greatly improved with neoadjuvant therapy: 3-year estimates were 83.2% compared to 71.6%. This first trial of neoadjuvant oncolytic virus therapy is therefore showing encouraging results and warrants continued evaluation.

Study compares neoadjuvant options for non-small cell lung cancer

Combined neoadjuvant chemo-immunotherapy therapy achieves superior downstaging of resectable non-small cell lung cancer as compared to chemotherapy, mono or dual immunotherapy

As neoadjuvant approaches with immunotherapies are gaining attention, Boris Sepesi, MD (MD Anderson Cancer Center), and colleagues compared outcomes with four treatment options: platinum doublet chemotherapy, nivolumab, nivolumab + ipilimumab, or nivolumab + doublet chemotherapy. The patient cohorts were pulled from institutional records and the NEOSTAR study, and were diagnosed with stage I-IIIA NSCLC.

The highest rate of overall clinical-to-pathological downstaging (ypT and/or ypN) was found in the cohort of patients treated with nivolumab and chemotherapy at 68%, while all three other treatment options led to overall downstaging rates of 38% (p=0.048). Upstaging rates also favored patients receiving nivolumab and chemotherapy, as only 14% of these patients were upstaged at the time of surgery, compared to 28% of the chemotherapy cohort and 38% of patients in both the nivolumab and nivolumab + ipilimumab cohorts. The only evaluation that did not favor the nivolumab + chemotherapy treatment was the ypN downstaging, where the lowest rate of downstaging (42%) was seen with this treatment and the highest rate (55%) with chemotherapy. While these downstaging rates are encouraging, it remains to be seen whether these rates in small cohorts extend to improved survival.

Combination nivolumab and intratumoral therapy may be promising neoadjuvant option for melanoma

Phase II Trial of Neoadjuvant Nivolumab (Nivo) and Intra-Tumoral (IT) CMP-001 in High-Risk Resectable Melanoma (Neo-C-Nivo): Final Results

Diwakar Davar, MD (UPMC Hillman Cancer Center), discussed a trial of combination nivolumab and intratumoral CMP-001 (a CpG packaged in a virus-like particle) in patients with high-risk resectable melanoma. Thirty patients were treated with a combination of neoadjuvant and adjuvant therapy. The neoadjuvant portion included seven weeks of weekly CMP-001 delivered intratumorally after the first week and three doses of nivolumab. After resection, nivolumab and CMP-001 were dosed every four weeks for 48 weeks. Primary goals of the study were to evaluate major pathological response rate and safety.

All but one patient completed the full neoadjuvant therapy cycle, with two patients discontinuing CMP-001 due to toxicity. Radiographic analysis indicated response in 43% of patients and stable disease in 30%. Pathologic responses included complete response in 50%, major pathologic response in 10%, and partial response in 10%. Biomarker analysis indicated that responding tumors had increased levels of CD8+ TIL and CD303+ plasmacytoid dendritic cells. The median relapse-free survival has not been reached in patients with pathological responses, leading the investigators to continue further investigation of this combination.