Replies to post #35387 on OncoSec Medical Inc (ONCSQ)

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Novel T-Cell Exhaustion Markers to Predict Response to Anti-PD-1 Monotherapy? Yes, It Seems So...
@maximgrp.com
@maximgrp.com
Summary:
OncoSec's collaborators at the University of California San Francisco presented results today at ASCO demonstrating the utility of a T-cell exhaustion marker to predict response to anti-PD-1 monotherapies.
The combination of OncoSec's ImmunoPulse IL-12 and pembrolizumab is the first clinical trial to use this assay to select specific patients, who are unlikely to respond to monotherapy with anti-PD-1 agents.
Using samples from prior trials, authors of the poster presented results from a total of 53 patients evaluable for both response and the T-cell exhaustion marker (TEx). Fifteen patients were treated with a combination of ipilimumab and nivolumab, and 38 with monotherapy anti-PD-1. Patients determined to be "low-TIL" (TEx ≤20%) had 0/12 (0%) responses to anti-PD-1 therapy, while patients who were "high-TIL" (TEx >20%) had 21/26 (81%) responses. Median TEx was 40.3% for responders and 16% for non-responders. Using a threshold of TEx at 20%, the negative predictive value for response was 100% and the positive predictive value was 81%. For patients treated with the combination of ipilimumab and nivolumab, the TEx threshold predictive of response was much lower.
The authors conclude that the "T-cell exhaustion marker " is an accurate predictor of response to monotherapy, but not response to combination therapy with ipilimumab and nivolumab.
Details:
IL-12, a powerful immune modulator. IL-12 is regarded as the most potent cytokine for stimulating an anti-tumor response. The major challenge for using IL-12 is that it cannot be directly injected into patients due to its toxicity and its short half-life. Several companies are developing novel approaches to bring IL-12 to the tumor microenvironment, including Celsion (CLSN - $1.38 - Buy), Oncosec, Juno (JUNO - $46.82 - Buy) and Inovio (INO - $11.08 - Buy). This approach is particularly attractive for ovarian cancer, melanoma, HPV-driven cancers, breast cancer and lung cancer as these tumors are highly immunogenic, meaning there are T cells and other immune cells primed and ready to attack if given the signal (either naturally, by vaccine or by adoptive cell therapy (i.e. CAR-T, TCR).
Evaluating an anti-PD-1 combination. Oncosec presented compelling scientific data showing that Intratumoral IL-12 expression could potentiate tumor responses to anti-PD-1 therapy. Many patients with metastatic melanoma or SCCHN (or possibly other solid tumors) are anti-PD-1 non-responders so the therapy doesn’t work. Why? Likely due to a lack of TILs from PDL-1 production by the tumor masking itself from immune detection. Recent data have suggested that TILs are necessary for anti-PD-1 therapy. As such the poster/paper today suggest it may be possible to identify a "combination efficacy signal," which will enrich outcomes in Oncosec's current single arm study.
IL-12 Immunopulse has been shown to increase TILs, and in the absence of an anti- PD-1 still generates a significant anti-tumor response (melanoma trial), meaning that IL-12 could convert a non-responder phenotype to a responder. This suggests that IL-12 paired with anti-PD-1 could potentially enhance tumor cell killing; combining a T cell effector agent with a T cell function/production agent could be a powerful immunotherapy approach with applications to many tumor types.