On August 15, 2016 OncoSec Medical Incorporated ("OncoSec") (NASDAQ: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, reported the publication of research showing that partially exhausted CD8+ cells infiltrating melanoma tumors accurately predicted most patients’ responses to anti-PD-1 therapies (Press release, OncoSec Medical, AUG 15, 2016, View Source [SID:1234514587]). The findings, published in the Journal of Clinical Investigation, show that the response to pembrolizumab strongly correlated to the percent of CD8+ tumor-infiltrating lymphocytes (TILs) that expressed high levels of both PD-1 and CTLA-4. The study was led by University of California, San Francisco (UCSF) researchers and physicians. This exhaustion marker is currently being used to select patients for the ongoing Phase II investigator-sponsored clinical trial evaluating the combination of OncoSec’s investigational therapy, ImmunoPulse IL-12, and the approved anti-PD-1 therapy, pembrolizumab, in patients with unresectable metastatic melanoma.

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With tumor samples from a discovery cohort of 20 patients who had received anti-PD-1 therapy, researchers used multiparameter flow cytometry to sort cells according to immune biomarker expression in the study. Researchers examined CD8+ cells to see whether they expressed PD-1, CTLA-4, and other proteins. The number of partially exhausted CD8+ cells in tumors that expressed high levels of both PD-1 and CTLA-4 was a reliable biomarker of response to anti-PD-1 therapy, with response defined by standard RECISTv1.1 criteria. This observation was confirmed in a separate validation cohort of 20 patients.

"This paper supports the concept that the ‘target cell’ of anti-PD-1 monoclonal antibodies (mAb) is the partially exhausted CD8+ T-cell within the tumor, which can be readily quantified using flow cytometry," said Robert H. Pierce, MD, OncoSec Chief Scientific Strategist and co-author of the paper. "We’ve taken advantage of this assay’s ability to strongly predict patients, who are unlikely to respond to anti-PD-1 mAb monotherapy, and select these patients in our ongoing Phase II trial, where we are combining intratumoral electroporation of plasmid IL-12 and pembrolizumab."

"These findings represent an advance in the field of cancer immunotherapy," said Adil Daud, MD, director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center. "Many tests examining PD-L1 levels in tumor tissue can only modestly discriminate between responders and non-responders. This analysis accurately predicts response to anti-PD-1 therapy and can be utilized in the clinic to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition."

OncoSec is assessing the anti-tumor activity, safety, and tolerability of the combination of ImmunoPulse IL-12 and pembrolizumab in melanoma patients in a Phase II clinical trial sponsored by UCSF. This multi-center, open-label, single-arm trial is the first study to use UCSF’s T-cell exhaustion marker assay. The study will test the hypothesis as to whether the addition of ImmunoPulse IL-12 to pembrolizumab can increase the response rate in melanoma patients, who have a low likelihood of responding to monotherapy with anti-PD-1 blockade. The key endpoints of the study include: best overall response rate (BORR) by RECIST v1.1 and immune-related Response Criteria (irRC); safety and tolerability; duration of response; 24-week landmark progression-free survival; median progression-free survival; and overall survival. OncoSec expects to present data from this trial in the second half of 2016.