OncoSec Medical Inc (ONCSQ)

[hschlauch]

https://www.medpagetoday.com/reading-room/asco/immunotherapy/69883

Whole-body immune priming with in situ vaccine improves response in refractory patients
SAVESAVED

by Mark L. Fuerst
Contributing Writer, MedPage Today

[quote

Advanced melanoma patients who do not respond to programmed death-1 (PD-1) inhibitors show promising responses to a combination of an immune primer plus anti-PD-1 therapy.

The study demonstrates that it is possible to generate whole-body immune priming using an in situ vaccination approach with minimal systemic side effects.

"Injecting an interleukin[IL]-12 plasmid and then electroporating tumors led to an increase of anti-cancer immune signals and immune cells in the tumor and throughout the body," the study's lead author, Alain Algazi, MD, of the University of California San Francisco, told MedPage Today. "This effect was even more pronounced when tavokinogene telseplasmid was administered in combination with the PD-1 antibody pembrolizumab, even though we selected patients for the study who were predicted to be non-responders to pembrolizumab monotherapy."

The PD-1 antibodies pembrolizumab and nivolumab have enabled thousands of metastatic melanoma patients to achieve long-lasting remissions with relatively few side effects, but these agents do not work in the majority of metastatic melanoma patients, he explained. "The bottleneck for response in many patients is a lack of intratumoral immune cells and immune signals -- that is, an immunologically 'cold' tumor. If we can convert these 'cold' tumors into 'hot' tumors with anticancer immune cells and signals, we can help patients who would not otherwise respond to PD-1 monotherapy achieve long-term remission."

There is an unmet medical need in patients with melanoma who are refractory or have relapsed on anti-PD-1 therapies. "Patients who do not respond to PD-1 antibody monotherapy have few options, with a significant chance of inducing long-term remission," Algazi continued. "BRAF-inhibitor combinations have a median progression-free survival of less than 1 year in BRAF-mutant melanoma patients. The combination of nivolumab and ipilimumab may capture additional responses, but there is a high risk of severe toxicity -- 70% grade 3 and 4 adverse events -- so this option is not appropriate for many patients."

Previously, studies showed that intramural delivery of plasmid IL-12 by electroporation can reshape the tumor microenvironment, transforming both treated and untreated lesions into CD8+ T-cell inflamed tumors. Earlier studies showed that the combination of pembrolizumab and intratumoral plasmid IL-12 held promise in stages III/IV melanoma patients.

Algazi presented data from recently completed phase II monotherapy and combination therapy studies at the 2017 World Congress of Melanoma (Abstract P524). The OMS-I100 monotherapy study included 51 patients and the OMS-I102 combination study included 22 patients, all with metastatic melanoma. The combination-study patients were selected based on their baseline biomarker data, which predicted that patients would not respond to anti-PD-1 therapy. Patients must have had histological or cytological diagnosis of melanoma with locally advanced or metastatic disease that was not amenable to definitive local therapy and at least one measurable tumor accessible for intratumoral injection.

Monotherapy patients were treated with IL-12 injections alone on days 1, 5, and 8 of every odd cycle at 6-week intervals. In the combination study, patients received IL-12 injections plus 200 mg intravenous infusions of pembrolizumab every 3 weeks.

At 24 weeks, the best overall response rate in the combination arm was 50% (11 of 22 patients). This included 41% of patients with a complete response and 9% of patients with a partial response. Another 9% of patients achieved stable disease, for a total disease control rate of 59%. In the monotherapy arm, about one-third of patients achieved a best overall response rate.

The progression-free survival rate at 15 months was 57%; among responders, the duration of response was 100%.

Fewer than 10% of patients in both studies reported treatment-related serious adverse events (9.8% in the monotherapy arm and 8.7% in the combination arm).

"We have demonstrated that intratumoral therapy with pembrolizumab can help many patients who would not be helped by PD-1 antibodies alone, including patients with prior exposure to ipilimumab, PD-1 antibodies, or both," said Algazi.

In addition, biomarker data highlights the positive impact of the combination therapy on immunological mechanisms. "Responding patients had a significant treatment-related increase in the density of intratumoral CD8+ T cells coupled with a significant increase of intratumoral Th1-related gene expression."

Intratumoral T-cell receptor (TCR) clonality significantly increased after a single cycle of treatment. "Responders who had low peripheral TCR clonality had significantly higher intratumoral TCR clonality after treatment, but in non-responders, this relationship was inverted with no significance noted," he said.

Durable clinical responses continue to demonstrate that this combination therapy is a promising treatment modality. "The updated correlative immune-focused biomarker data further highlights that this IL-12-based therapy can drive intratumoral Th1 polarization and an increase in CD8+ tumor infiltrating-lymphocytes."

The increased treatment-related intratumoral TCR clonality and proliferating exhausted T cells in the periphery of responding patients extends the concept that intratumoral injections plus pembrolizumab can reshape the tumor microenvironment, Algazi noted. "Collectively, these data suggest that combination intratumor therapy plus pembrolizumab directs the tumor microenvironment towards a Th1 immune phenotype with reduced immune suppression. The robust intramural and systemic anti-tumor response supports improved clinical outcomes in patients predicted not to respond to anti-PD1 therapy."

The next step, he said, is a multisite phase II clinical trial focusing exclusively on patients with documented resistance to PD-1 antibodies. "A definitive randomized phase III trial is also in the planning stages. In parallel, we are developing an additional study for patients with advanced squamous cell carcinoma of the head and neck, with more details regarding this to be available soon. Our findings need to be confirmed, but this new treatment approach could help metastatic cancer patients to achieve long-term remission with an acceptable side-effect profile/quote]