The Sentinel


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.

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