Spotlight on Shivani Srivastava

Improving Cancer Immunotherapies

Shivani Srivastava, Immunologist

Dr. Shivani Srivastava grew up in an academic family. She remembers spirited debates between her grandfather, uncles, and father — a mix of math professors and engineers by training.

“Something would be bothering them, a question would keep them up at night and chew at them. [I remember them] discussing it and arguing about it at the dining table,” she said. “And then when they figured something out together, they’d be so satisfied.”

Srivastava had always been interested in human disease, but didn’t expect to forge a career trying to overcome it. Initially, like her father and grandfather, she was more attracted to math and chemistry than biology.

But a genetics class in high school started to shift her interest.

“I found the idea that all these aspects of human life can be distilled down to your DNA really interesting,” Srivastava said.

So Srivastava took a risk on biology in college. But after two years of core classes, which leaned heavily on memorization, she feared she’d made a mistake. A chance elective saved her.

Srivastava, who is now an expert on a type of immune cell called a T cell, first took an immunology class because it fit her schedule best. But the class changed everything. Rather than teaching from a textbook, the professor guided her students through the discoveries and seminal papers that had advanced scientists’ understanding of the immune system.

Dr. Shivani Srivastava at her computer
Dr. Shivani Srivastava studies the immune system to find ways to improve immunotherapy. Robert Hood / Fred Hutch News Service

“That way of teaching biology from the perspective of the researchers — that really nailed it down for me,” Srivastava said. “Immunology is at center of so many real-world situations: whether you clear an infection or get autoimmunity, or how you handle a tumor. Your immune system handles really complicated tasks — any time you’re able to figure out some mechanism, it’s like solving a real-world puzzle.”

For researchers interested in making foundational discoveries and improving human health, immunology is the best of both worlds, she said. The field is rich in basic science questions still to be answered, and any advance has the potential to help improve human health.

“I think everybody wants some kind of real-world application” for their research, she said. “With immunology, it’s so simple to understand [what that is]. This is something your body’s doing on a daily basis.”

Her current work focuses on T cells, a type of immune cell that’s able to kill diseased or infected cells. Researchers have engineered T cells to help develop new cancer immunotherapies, called adoptive T-cell therapies. The Food and Drug Administration has approved several examples of a specific type of engineered T cell, known as a chimeric antigen receptor T cell, or CAR T cell, for use against certain blood cancers.

“The goal is to understand the mechanisms shutting down T-cell function, and then see if we can use our engineering strategies to make T cells resist them.”

Scientists want to extend these successes to solid tumors like breast and lung cancer. Research has shown that patients with a robust T-cell response against their solid tumors often fare better than patients whose immune systems aren’t mounting a good anti-cancer response, but so far results using engineered T cells against solid tumors have been disappointing. Often the T cells fail to even enter the tumors, let alone mount an attack. Those that do make their way inside often attack lethargically — if they survive long enough to attack at all.

Srivastava works to understand how T cells normally find and attack diseased cells successfully, and how biological mechanisms underlying these functions can be manipulated by scientists to develop more effective CAR T-cell therapies against solid tumors. To do so, she develops mouse models of solid tumors that better mimic the human form of the disease. Then, she uses these models to parse how the tumors tamp down CAR T-cell function and test strategies to overcome these barriers.

T cells integrate many signals as they decide which cells to destroy and which to spare. Currently, CAR T cells only employ a few of these signals. Srivastava aims to make engineered cell therapies safer and more effective by figuring out the key signals that drive natural T cells’ responses, and how to incorporate them into CAR T cell therapies.

“One of the advantages with adoptive T-cell therapy is that we have a lot of engineering strategies,” she said. “The goal is to understand the mechanisms shutting down T-cell function, and then see if we can use our engineering strategies to make T cells resist them.”

— By Sabrina Richards, March 24, 2021