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Unlocking Cell Therapy in Pediatric Diseases: A Conversation with Crystal Mackall

In a conversation with OTL, Dr. Crystal Mackall highlights the most challenging and fulfilling parts of her work.
Photo of Dr. Crystal Mackall
Dr. Crystal Mackall

Dr. Crystal Mackall’s name and accolades- as well as her three startups- are synonymous with cancer cell therapy at Stanford. In a conversation with OTL, she highlights the most challenging and fulfilling parts of her work- the promise that cell therapy brings to pediatric patients, and the difficulty in developing therapies for those most in need.

Since joining Stanford’s School of Medicine in 2016 as a Professor of Pediatrics and Medicine, Dr. Mackall has led a robust research lab focused on harnessing patients’ T-cells to fight cancer. While T-cells are natural tumor cell fighters, unleashing the immune system can create strong inflammatory states that must be carefully controlled. Meanwhile, certain tumors are better able to evade T-cell surveillance, and need an extra boost to zero-in on their target. This give-and-take on T-cell function must be fine-tuned to selectively ramp up T-cell activity only where it is needed most.

The Mackall lab has been a pioneer in introducing modifications to a cancer patient’s T-cells that enable the immune system to attack cancerous cells vigorously and specifically, threading the needle for appropriate levels of T-cell activity. The group is developing a cadre of cell engineering tools to increase the potency of T-cells, while also limiting toxicity of the immune attacks. This brave new world of optimized engineering also includes regulatable immune cells that can be controlled with a small molecule, bringing a comforting level of dosing control to potentially unwieldy cell therapies.

“Scientists have been learning how to tune the cells,” Dr. Mackall said. “Instead of letting them do the hundred-meter dash, we're training the cells for the marathon, and that requires some tuning and some rest. And it turns out that giving the cells rest is very restorative and allows them to be in there for the long haul.”

Those modifications are paying off, as six chimeric antigen receptor (CAR) T-cell therapies have been approved by the FDA since 2017, with all current approvals targeting hematological malignancies.
But while cell therapy is continuing to accumulate commercial traction, challenges remain in securing access to these new developments- particularly for pediatric diseases. While 80% of pediatric cancers are curable, albeit often with lifelong side effects, the remaining 20% of patients face a grim prognosis.

“We've had a market failure in the realm of pediatric cancer in the last thirty years,” Dr. Mackall says. “We're treating children today for cancer the way we treated them in the 1970s and 1980s.”
This comparative lack of biopharma investment in pediatric oncology is couched in the risk profile for the setting, where “children’s cancers are wired differently than adult cancers”- and therefore don’t benefit from the foundational discoveries made in the adult setting.

“Even when the academics come up with a great drug for a children's cancer, we can't get the doggone thing commercialized,” Mackall said.
Academic centers like Stanford’s Laboratory for Cell and Gene Medicine (LCGM) could offer a solution to this dearth in commercialization; housed in the School of Medicine, the facility offers cGMP manufacturing of cell and gene therapy products suitable for Phase I/II studies, allowing academic labs to continue the de-risking of therapeutics even in the absence of a commercial partner.  Dr. Mackall is a co-executive director of LCGM, where up to ten preclinical and clinical partnerships are in progress across a wide range of treatment modalities.

Mackall says that the LCGM has been “absolutely transformational for the field,” helping to unlock new biological insights.

“When you do these trials at an academic medical center, not only can you more rapidly move something into the clinic than you can potentially using the industry model, but you learn so much from every patient because we are able to leverage all the resources of the institution to study the patients. We learn the weaknesses, we learn how the cells fail, and then we can iterate and go back to the bench and create the next generation.”

This route allows academics and research centers the opportunity to step in where traditional biopharma has remained on the sidelines, conducting their own de-risking research, and potentially offering direct patient access in the future. Dr. Mackall argues that the future of cell therapies for small markets like pediatric cancers could be point-of-care manufacturing, where local hospital systems like Stanford could fill in the gaps left by missing biopharma partners and conduct their own on-demand production of cell therapies. 

“The hospitals have to be part of this, and I really believe and hope that the regulatory bodies and the commercial landscape will be such that we can leverage the deep expertise within our academic medical centers with cell therapies for the benefit of our patients,” Dr. Mackall said.