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.