Tumor-Agnostic Therapy for Anti-PD-1 Nonresponders

OncoSec Medical’s Tavo, a DNA-based interleukin-12 immunotherapy that is delivered to tumors via electroporation, is currently in Phase II trials

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Checkpoint inhibitors provide viable treatment alternatives to radiation or chemotherapy for patients with solid tumors, but they are effective in only 15–30% of patients. To improve the checkpoint inhibitor response rate, OncoSec Medical is developing a novel tumor-agnostic therapy. The therapy, called Tavo (tavokinogene telseplasmid), is designed to help patients who do not respond to checkpoint inhibitors.

Tavo is a DNA plasmid that encodes interleukin-12 (IL-12), a cytokine that signals inflammation. Studies suggest that it is effective as an immunotherapeutic when administered in combination with a checkpoint inhibitor or even as a monotherapy, providing clinical responses regardless of whether the treated tumors are “hot” or “cold.”

An unusual mechanism

Some cancers evade detection by the immune system by engaging PD-1, an immune checkpoint that serves as an on/off switch for antitumor T cells. “Checkpoint inhibitors prevent the T cells’ on/off switch from being turned off,” explains Daniel J. O’Connor, president, CEO, and director of OncoSec Medical. “It’s like putting a cover over the switch.
If the tumor is immunosuppressed or immunologically excluded, though, checkpoint inhibitors won’t have much success.”

This is where Tavo comes into play. “We inject Tavo into one or a few tumors,” O’Connor says. “By deploying a DNA plasmid that encodes IL-12 into the cancer cells, we force the tumor to make IL-12.” The cancer cells signal inflammation, and like the immune messages instigated by vaccines, the proinflammatory message instigated by IL-12 spreads systemically, attracting T cells to tumors and increasing the number of tumor-infiltrating lymphocytes.

When Tavo is administered as part of a strategy that includes a checkpoint inhibitor, such as Keytruda (pembrolizumab), the two therapies work together to systemically attack immunosuppressive tumors, ultimately shrinking them as well as distant, untreated tumors.

Encouraging findings

Interim data from the Keynote 695 study, published last November, assessed about 50 patients with metastatic melanoma who were actively progressing on checkpoint inhibitor therapies. When patients were treated with Tavo plus Keytruda, almost 30% had a clinical response. “These powerful effects are not transient,” O’Connor asserts. He points out that at the time of the analysis, the median duration of response exceeded 12 months.

Daniel J. O’Connor
Daniel J. O’Connor
President, CEO, and Director
OncoSec

“Now we are waiting for the remainder of the 100 patients [to be assessed], and we expect to have that readout toward the end of the year,” he adds. “We evaluate tumor size every three months. Tumors must shrink 30% from baseline after three months, and be confirmed at six months, before we consider the patient a responder.”

An energy pulse emanates from a small device that is briefly inserted into the tumor. “When the energy pulse ceases, the cells return to normal,” O’Connor notes. The tumor cells then have the instructions to make IL-12, avoiding the toxicity normally associated with systemically delivered IL-12. What begins as a local response quickly develops into a systemic response.

Tavo is unique not just in terms of introducing IL-12 into the tumor cell, but in terms of how that introduction occurs. Rather than encapsulating the DNA-based therapeutic in a carrier such as a nanoparticle or adenovirus vector, OncoSec uses electroporation technology. That is, the company uses radiofrequency energy to temporarily increase the permeability of the cell so that the plasmid IL-12 can slip inside.

Once the cells are transfected, they make IL-12 for 7–10 days and trigger a natural “handoff” of endogenous production of IL-12. The handoff occurs as the IL-12 derived from the DNA-encoded therapeutic begins to wane. “We inject the tumor on days one, five, and eight, and then stop for six weeks before starting the cycle again,” O’Connor details. The process initiates a whole-body (abscopal) effect.

This therapy has both orphan and fast-track designation in the United States for patients with metastatic melanoma. The next milestone is the completion of a Phase II study in metastatic melanoma. (At present, this study is fully enrolled.) Subsequent milestones include the completion of two other Phase II studies, one for triple-negative breast cancer, and one for head and neck cancer.

A new challenge

O’Connor became involved in OncoSec in 2017, five years after the company was founded. “I was called by the company to look at the data,” he recalls. “The more I looked, the more I liked what I saw.”

At the time, he had just left an immunotherapy-focused company called Advaxis. He wasn’t certain he wanted to take on another job so soon. So, he joined OncoSec’s board of directors. Three months later, he became OncoSec’s CEO.

The early days were filled with challenges. “I guess that’s why they call it ‘work,’” he quipped. “Patients were not actively enrolling in the only clinical study that the company had open at the time. We had a lack of capital and needed staff, but the backbone of the company—its technology—was solid.”

At present, clinical activity is intensifying. “We have several important clinical trials underway, great clinicians leading those trials, and company leaders who have track records of successful drug approvals and commercial launches in the key functional areas,” O’Connor relates.

Having achieved financial stability, OncoSec Medical is now able to focus on its therapeutic mission. “The real meat of what we do every day is run clinical and feasibility studies, collect and analyze data, and manage all the pieces of the puzzle involved in developing a therapy,” O’Connor remarks.

He adds that the company’s mission includes putting the “right people in the right jobs and keeping them well supported, happy, and focused.” Even when individual focus is steady, organizational focus can be challenging, he admits, particularly since “there’s an abundance of things we could do.”

The company is already busy with ongoing trials, and it is planning to bring another product—Tavo with CXCL9, a chemokine—to the clinic “this year or next,” O’Connor says. “We’d like to do many other meaningful clinical studies as soon as possible.”

OncoSec’s Tavo, a DNA plasmid that encodes interleukin-12 (IL-12), is designed to turn a tumor “hot” and reinforce checkpoint therapy. After Tavo is injected directly into a tumor, a needle array from the tip of an electroporation applicator is inserted into the tumor. Next, the applicator supplies a series of electrical pulses, helping the plasmids enter the cells. The DNA-based IL-12 is expressed in the cells and released into the local tumor microenvironment.

Versatility, he muses, can be both a strength and a weakness. “With a highly versatile platform technology comes the potential for many different anticancer applications, which can be a distraction,” O’Connor continues. “We naturally want to do many things, but we know that we can’t. Therefore, we are forced to be very focused and disciplined in terms of what genes are being used and which cancers are being targeted.”

Lofty goals

O’Connor’s immediate goals for OncoSec are to finish the checkpoint refractory metastatic melanoma study currently underway and to communicate the results to regulators and other constituencies. The ultimate objective is to see Tavo used in patients. The company is seeking positive outcomes such as operability, pathologic tumor response, and long-term disease control in early melanoma patients.

“The safety exposure and patient experience are unlike any I’ve ever seen,” O’Connor declares. Cellulitis—the main side effect—is very rare. “You can never say any drug works until it is approved,” he concludes, “but the clinical observations so far are encouraging.”

If approved, this approach has the potential to dramatically improve the outcome of patients with solid tumors who otherwise can’t benefit from revolutionary checkpoint immunotherapies.

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