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Immunotherapy and treatments such as checkpoint inhibitors like anti-PD-1 are the mainstay of the anti-cancer arsenal. However, a significant subset of patients with solid tumors—including melanoma—do not respond to this form of checkpoint therapy. This has stimulated a search for more effective approaches, including combination therapies.

One proposed strategy involves combining standard intravenous anti-PD-1 treatment with the intratumoral delivery of a DNA fragment (plasmid) encoding a naturally occurring protein with immune stimulating functions, called interleukin-12 (or IL-12). Electroporation permits the IL-12 plasmid to enter cells and to elicit an anti-tumor T-cell response within the tumor. This shift in the tumor from “cold” tumor depleted of T-cells, to a “hot” tumor replete with T-cells, makes it more likely to respond to anti-PD-1 therapy. Consequently, the immune system is better equipped to target and attack cancer cells. The immune attack is focused as both local and distal, widespread despite limited systemic exposure to the drug.

A unique approach

Engineered DNA, designed to code for immune-stimulatory proteins, can be administered or electroporated directly into one or more tumors. The needle applicator supplies a sequence of short-duration electrical pulses to the tumor, transiently increasing permeability of the cell membrane and facilitating uptake of the DNA-based agent. The cell membrane subsequently reseals and the electroporated cells manufacture the protein according to the specifications engineered into the DNA-based agent. Expression of immunomodulatory cytokines, antibodies and other proteins can be expressed in-situ. pIL-12 (plasmid interleukin-12) is a human gene that is injected directly into a tumor, thereby forcing the tumor to produce IL-12 protein, a strong proinflammatory immune activator. Electroporation is a small electrical current applied directly to a tumor, which allows the IL-12 gene (plasmid) to readily enter these tumor cells. In a majority of individuals, pIL-12 has been shown to increase the number of tumor infiltrating lymphocytes (TIL), a critical type of white blood cells (immune cell) that help fight the tumor. An increase in these CD8+ TIL may help individuals to respond better to immune checkpoint inhibitors, like anti-PD-1.

What is the relevance of this approach as a combination therapy? ImmunoPulse IL-12 therapy is a gene-based (DNA) therapeutic that can direct a treated tumor to produce a strong immune-activating protein, which helps recruit an army of CD8+ T-cells to the tumor (step one of an effective anti-PD-1 therapy). In response to these freshly recruited CD8+ T-cells, tumors increase their levels of PD-L1 (step two of an effective anti-PD-1 therapy), which bind to PD-1 on the surface of T-cells, applying an “immunological brake” and diminishing the T-cell’s anti-cancer capabilities. The addition of anti-PD-1 blocks the immune suppressive interaction between PD-1 on the T-cell and PD-L1 on the tumor (step three of an effective anti-PD-1 therapy), allowing for a maximal anti-tumor T-cell response. Thus, combining ImmunoPulse IL-12 with anti-PD-1 allows each component to work optimally.

Clinical study data

In February 2017, OncoSec Medical Incorporated reported new positive clinical data from a Phase II investigator-sponsored clinical study assessing the combination of its investigational intratumoral therapy, ImmunoPulse= IL-12, and the approved anti-PD-1 therapy, pembrolizumab, in patients with unresectable metastatic melanoma. The results of this single-arm, open-label study, which was led by the University of California, San Francisco, and the Huntsmann Cancer Institute in Utah, indicated that the therapy can increase objective response rates in patients who are not expected to respond to anti-PD-1 therapy alone.

The study is evaluating the following key endpoints: best overall response rate (BORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune-related Response Criteria; safety and tolerability; duration of response; 24-week landmark progression-free survival (PFS); median PFS; and overall survival (OS).

The study results showed an overall response rate (ORR) at 48 weeks of 43 percent (9/21) and BORR of 48 percent by RECIST v1.1. There were 24 percent (5/21) complete responders, 19 percent (4/22) partial responders and nine percent (2/21) stable disease for a total disease control rate of 52 percent (11/21). These data are consistent with, and expand upon, previously reported preclinical and clinical data that provide a compelling rationale for combining the IL-12 therapy with anti-PD-1 blockade.

Collectively, the data suggest that intratumoral pIL-12 administered by electroporation and given in combination with pembrolizumab can effectively alter the tumor microenvironment. This increases the substrate for a therapeutic PD-1 blockade while driving systemic anti-tumor immunity and concordant clinical responses in patients unlikely to benefit from anti-PD-1 monotherapy.

Other potential applications

The study of ImmunoPulse IL-12 in combination with anti-PD-1 treatment is merely one of several applications of this approach. There still remains a large number of non-responders who may benefit from the same combination approach in other forms of cancer such as triple negative breast cancer (TNBC) and head and neck cancer.

Taking the fight directly to the tumor and harnessing the power of the body’s immune system to recognize and attack cancer appears to be bearing fruit so far, with promising preliminary efficacy and safety data from clinical studies. At a time when the promise of immunotherapy is widely appreciated but the next steps for effective treatment are still being determined, combination therapy is an approach worth continuing to pursue.

The results obtained to date encourage a new vision in the immunotherapy landscape—one that can potentially capitalize on the ability of local therapy to drive a systemic anti-tumor immune response and overcome some of the limitations of traditional treatments.

Sharron Gargosky is Chief Clinical & Regulatory Officer of OncoSec Medical Incorporated, a biotechnology company developing DNA-based intratumoral immunotherapies with an investigational technology, ImmunoPulse®, for the treatment of cancer.

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