Melanoma is one of the most dangerous forms of skin cancer.  Based on recent data from the American Cancer Society, the disease accounts for the vast majority of skin cancer deaths. [1]

When melanoma is caught early enough, surgical excision can be curative in the majority of stage I and II melanomas. The overall 5-year survival rate for patients with localized melanoma is 98% in the United States.[1] At later stages, malignant melanoma remains a deadly and frequently difficult to treat cancer. The overall 5-year survival rate for patients falls to 17% when the disease metastasizes to distant sites or organs.[1] Approximately 8,780 patients are diagnosed with stage III and IV melanoma in the United States each year.[2]

© AACR/Used with permission

Melanoma that has spread to distant sites may be treated with surgery, immunotherapy, chemotherapy and/or radiation therapy.[1] Numerous chemotherapy regimens have been tested in melanoma with only modest success and limited overall survival benefit. [3] Immunotherapies, such as checkpoint inhibitors, have demonstrated improvement in overall survival of patients compared to chemotherapy.[3]

No response
While immunotherapy can be extremely effective, the majority of patients will not respond to anti-PD-1 therapy alone, representing a great unmet need in oncology. However, researchers are focusing efforts on targeting pathways of T cell activation.[4] The presence of CD8+ T cells seems to correlate with improved prognosis and long-term survival in solid malignancies, such as melanoma, [5][6] thus many emerging experimental immunotherapies seek to enhance the tumor’s immunogenicity and increase the anti-tumor CD8+ T cell response.

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PD-1/PD-L1 blockade
Long-term, follow-up data of patients who were treated with an investigational therapy ImmunoPulse™ IL-12, being developed by San Diego-based OncoSec Medical, a biotechnology company developing DNA-based intratumoral cancer immunotherapies, went on to receive an anti-PD-1/PD-L1 therapy. These data suggest that ImmunoPulse IL-12 may prime and enhance response rates to PD-1/PD-L1 blockade.

Alain Algazi, MD, skin cancer specialist in the Melanoma Center at the UCSF Helen Diller Family Comprehensive Cancer Center, presented the findings in an oral presentation entitled “Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma” (Abstract #CT134) at the annual meeting of the American Association for Cancer Research (AACR) in New Orleans, LA.

“We are encouraged by the data from this analysis, which show that intratumoral IL-12 DNA with electroporation can prime the immune system and help improve patient response to anti-PD-1,” noted Algazi.

“These results are being validated prospectively in a phase II clinical trial and they could make a clinically meaningful impact on patient outcomes and address a great unmet need in immune-oncology,” Algazi continued.

Single-site retrospective analysis
These new data were generated from a single-site retrospective analysis of the OncoSec Medical’s Phase II monotherapy clinical study of ImmunoPulse IL-12, which employs intratumoral electroporation to enhance delivery of DNA-based interleukin-12 (IL-12), in patients with advanced melanoma.

After completing treatment with ImmunoPulse IL-12, a subset of patients subsequently received an anti-PD-1/PD-L1 therapy either as their next line of treatment or a later line of treatment. Patients with documented follow-up history and evaluable for anti-PD-1/PD-L1 response were included in this analysis.

In this study, 34 patients were enrolled and treated with ImmunoPulse IL-12 alone. Fourteen of these 34 patients went on to receive a systemic anti-PD-1/PD-L1 therapy and were evaluable for PD-1/PD-L1 overall response rate (“ORR”) using immune-related response criteria.

The PD-1/PD-L1-associated ORR among patients was 64% (9/14). The analysis showed 36% of patients (5/14) had a complete response (CR), 29% of patients (4/14) had a partial response (PR), 14% percent of patients (2/14) experienced stable disease, and 21% of patients (3/14) had progressive disease. Furthermore, 8 of these 14 evaluable patients received a systemic anti-PD-1/PD-L1 antibody with no intervening therapy after treatment with ImmunoPulse IL-12. Of these 8 patients, an ORR of 75% was observed (50% CR and 25% PR).

Additionally, multiple biomarker analyses demonstrate that therapy promotes the generation of activated natural killer and functional T cell immune subsets in the periphery as well as CD8+ tumor infiltrating lymphocytes (TIL), which may help trigger the PD-1 immune checkpoint (i.e. “adaptive immune resistance”) to provide the “substrate” for effective anti-PD-1/PD-L1 therapy.

“Although one always needs to be cautious regarding the interpretation of retrospective analyses, these data are consistent with our hypothesis that ImmunoPulse IL-12 is driving a specific anti-tumor TIL response, which p ,” noted Robert H. Pierce, MD, Chief Scientific Officer.

“We look forward to following up on these observations with interim data from our ongoing combination trial in patients with melanoma investigating ImmunoPulse IL-12 and the anti-PD-1 therapy, pembrolizumab, later this year,” Pierce continued.

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