May 8, 2017

UConn doc's vaccine aims to fight ovarian cancer

HBJ PHOTO | John Stearns
HBJ PHOTO | John Stearns
Dr. Pramod Srivastava, seen in his lab at UConn Health, is conducting a phase one clinical trial for an ovarian cancer vaccine.
HBJ PHOTO | John Stearns
Dr. Pramod Srivastava shows a petri dish where an ovarian cancer patientís immune cells are cultured and mixed with her cancer cells.

UConn Health's Dr. Pramod Srivastava has opened a clinical trial for a personalized vaccine against ovarian cancer that he hopes proves its safety and effectiveness, sets the stage for commercial development and lays the groundwork for treating other cancers.

Ovarian cancer, for which there's no screening test, afflicts about 20,000 women in the U.S. each year and often doesn't present clear symptoms until reaching advanced, stage 3 or 4 levels. After surgery and chemotherapy, the cancer recurs in about 90 percent of patients within a couple years. Of those, most die.

"The idea is to give [patients] the vaccine after they've had their surgery and chemotherapy and see if we can prolong the time to recurrence or cure them altogether," said Srivastava, 61, director of the Carole and Ray Neag Comprehensive Cancer Center and Center for Immunotherapy of Cancer and Infectious Diseases at UConn Health, where he's worked since 1997.

Because ovarian cancer tends to recur predictably within a period of time, doctors can gauge the vaccine's effectiveness in fending off the disease, said Dr. Susan Tannenbaum, chief of the Division of Hematology & Oncology at the Neag cancer center, who will lead the clinical trial.

Srivastava's personalized immunotherapy technology uses genomic analysis, which studies an individual's unique DNA, to identify differences between a woman's healthy and cancerous tissue. A vaccine is then created to boost the patient's immune system and target the cancerous cells.

For a woman whose immune system is fighting, the vaccine aims to make it fight better; for a woman whose immune system isn't fighting, the vaccine will make it fight, Srivastava said.

"We make the vaccine based on each patient's tumor and immune composition. It's made for that woman from that woman's tumor information," Srivastava said.

The clinical trial is the world's first for a personalized ovarian cancer vaccine, according to Srivastava.

Advancements in genomic and computer analysis have made such targeted medicine possible, Srivastava said, noting each person has a genomic book in their body of six billion characters.

"So we take those six billion characters, the normal and the [tumor-inflicted ones], and we compare them and we say, 'ah, these are the ones' " that are most useful in helping determine which cells to target with the vaccine, he said.

Srivastava and his team create the individualized vaccine using samples of a patient's own DNA from both unhealthy cancer cells and healthy blood cells.

Scientists then sequence and cross-reference the entire DNA from both sources to pinpoint the most important genetic differences and then design the personalized vaccine — with the help of bioinformatics scientists, led by Ion Mandoiu of UConn's School of Computer Sciences and Engineering — to target specific genetic mutations of patients' cancerous cells, according to UConn Health.

Clinical trial

Successful tests in mice preceded U.S. Food and Drug Administration approval for human testing.

UConn is recruiting 15 women for the phase one trial — set to begin this month — who have their first diagnosis of ovarian cancer or first recurrence. Once a patient meets eligibility requirements, she'd have surgery to remove the tumor, followed by chemotherapy. During that roughly three- to four-month treatment, the key genetic mutations would be identified and the vaccine would be formulated.

After chemo recovery, the first patient would be vaccinated once a month, starting about Aug. 1, for six months, with blood drawn monthly to determine immune response. Future patients would follow the same routine, with the goal of adding about one patient a month to the trial over about 15 months.

"First thing we want to see is that it is safe," Srivastava said of the trial, then see if it's feasible, if there's an immune response or not and how long it takes for recurrence.

Assuming positive results, Srivastava would seek approval for a larger, randomized clinical trial that could take about four years and hopefully demonstrate effectiveness for approval to go to market.

The market potential is significant.

"My thought would be that the market penetration for something like this would be pretty high because there's huge demand and there's not much else available right now," Srivastava said.

Assuming 20,000 new ovarian cancer cases a year with 15,000 of those in advanced stage, and conservatively assuming 20 percent market penetration, that's 3,000 treatments. Conservatively estimating $100,000 per treatment, that's $300 million.

"This by itself would be a huge business opportunity," including for UConn and the state, he said.

The opportunity soars if the technology proves successful in trials against other cancers.

"In principle, this will apply to the big cancers — like breast, prostate, lung, colon, stomach — and so this trial is important not only for the market side of [ovarian cancer], but other much, much bigger [cancers]," Srivastava said.

He's talking with two potential investors about forming a company, in part, to raise capital for continuing R&D work.

Money raised so far includes $3 million from the Neags, $500,000 from Connecticut Innovations (CI) — the state's quasi-public venture arm — and about $200,000 from the Connecticut Institute for Clinical and Translational Science at UConn (CICATS).

CI committed funding last July. Half has been granted, with the balance contingent upon Srivastava reaching certain targets.

Successful technologies can generate licensing revenues for UConn and CI, which CI can reinvest in other research and companies. Companies located in-state also produce direct economic impact.

"Selfishly, we would like a Connecticut-based company to, if successful, get a chance to grow and develop the technology further in the state where CI can invest," said Dan Wagner, CI's managing director.

Assuming the technology translates across multiple cancers, "the market starts to open more and more," Wagner said.

Tannenbaum, who will supervise the trial's clinical aspect, said Srivastava is doing personalized immunotherapy in a new way, with technology that hasn't been utilized before in vaccine development. There are vaccines for different cancers in clinical trials, but the way they were engineered is different, she said.

"I think he's got just the kind of background and the kind of personality to potentially drive this to a place where it could actually work," Tannenbaum said. "Immunology, in my opinion, is really where cancer care is going and it's a privilege to work with him. If this works, it's all because of him."

Entrepreneurial roots

Srivastava is an experienced entrepreneur in cancer immunotherapy products. He co-founded and took public Agenus Inc., which makes cancer vaccines, and helped start Ikonisys, which does cancer detection, and Life Science Pharmaceuticals, which makes antibodies to cancer.

Dr. Cato Laurencin, CEO of CICATS and Van Dusen distinguished endowed chair and professor of orthopedic surgery in the UConn School of Medicine, said Srivastava's work is "absolutely brilliant" and called the doctor one of the pioneers of cancer immune therapy.

His novel vaccine for women with advanced ovarian cancer takes personalized medicine to the next level, Laurencin said.

"Dr. Srivastava is a very modest man," he said. His studies are "absolutely incredible and have an incredible potential to move things forward and bring it all forward."

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