Riding the Immunotherapy Wave of the Future
Crystal Mackall is joining forces with doctors and researchers who have a wide range of expertise to make Stanford a leading institution for cell therapies to treat cancer.
Today, most pills dispensed to patients — whether for diabetes, cancer or another disease — are made of synthetic proteins or other lifeless molecules. But in the future, infusions of living cells might become the go-to therapies for many conditions. Already, engineered immune cells have shown promise in treating a handful of cancers. And as the field takes off, Crystal Mackall, MD, a professor of bone and marrow transplantation, thinks Stanford has the potential to become a leader in these so-called cell therapies.
“Stanford already has a long history of being a leader in the field of cancer immunotherapy, but we’re at a point in time where the whole field is really exploding in terms of new ideas, new approaches and a wider array of diseases that can be targeted,” says Mackall. “So the program that I am leading will seek to really establish Stanford as a leader in all areas of cell therapy.”
Mackall’s goals don’t just hinge on her own research success; she’s bringing together researchers and clinicians from across Stanford in the effort.
Cell Therapies for Cancer
All cancers are characterized by abnormal, excessive cell growth. In most cases, these growths — which are best known as tumors — are caused by gene mutations that have accumulated in cells, keeping the cells alive and dividing when they wouldn’t otherwise. Because they’re rogue versions of cells from the patient’s own body, these cancer cells generally can evade detection and destruction by the immune system.
With cancer immunotherapy, though, scientists aim to ramp up the activity of the immune system so that it can hunt down and destroy cancer cells. Cell therapy — a subset of immunotherapies — uses altered or synthetic versions of immune cells to accomplish this.
“Cell therapy really is an area I believe is poised for rapid growth in terms of both clinical application and developing new technologies,” says Mackall. “Our ability to genetically engineer cells and use synthetic biology to direct at will the behavior of cells is in a really big growth phase right now, and Stanford’s strengths lie in many of those areas: human immunology, bioengineering and technology development. And all of those strengths can be brought together.”
Knowing that cell therapy works, the question is what its breadth of application will be, beyond cancers that affect B cells (cells of the immune system that are responsible for generating antibodies).
“It’s absolutely clear that cell therapy for B cell malignancies is here to stay,” she says. “The real question is what effect it will have on other diseases.”
Parker Institute for Immunotherapy
Earlier this year, Stanford announced the creation of a new center on campus as part of the Parker Institute for Cancer Immunotherapy, a multi-institution effort established with a $250 million grant from the Parker Foundation. Mackall, armed with an initial $10 million grant from the foundation, will be leading the Stanford center.
“Joining the Parker Institute will provide access to new immunotherapeutic drugs, immune monitoring platforms and collaborative clinical trials,” says Mackall. She’s already identified a cadre of researchers who will join the effort and has started designating funds to build new infrastructure.
Engineering New Receptors
Mackall focuses her own research on a type of cell therapy using chimeric antigen receptors (CARs). The engineered molecules are designed to include the best aspects of two other immunotherapies: antibodies and T cells (a type of immune cell).
“Antibodies are useful because they are highly specific and can be generated to target almost any molecule,” says Mackall. “And T cells are attractive because they’re so potent and durable.”
To treat a cancer with CARs, T cells are collected from the blood of a patient. Then the cells are engineered to have CARs on their surface that recognize the patient’s tumor. Next, they are cultured so that clinicians will have many more to use for treatment. When infused back into the patient, the new cells can seek out and kill the cancer cells they recognize.
Mackall has authored numerous papers using CAR T cells, including ones designed to bind to a molecule called CD19 that’s found on the surface of some tumor cells. Recently, she’s been involved in clinical trials of the cells to treat acute lymphoblastic leukemia (ALL) in children and young adults; the results of a phase 1 trial were published in The Lancet in 2015.
“The CD19 CARs have been just spectacular against ALL,” says Mackall, who is also a professor of pediatrics. “Response rates across several institutions have been in the range of 70 to 90 percent; I challenge you to find phase 1 trials of another cancer agent with that high a response.”
So far, CARs have been most successful for hematologic malignancies — leukemias and lymphomas. Scientists don’t know why the approach works better for blood cancers than solid tumors — like breast cancer or liver cancer — but that’s one question Mackall hopes to answer. She also wants to know why the method works so well for some patients but not for others.
Answering these kinds of questions, she says, requires back-and-forth cooperative efforts between bench scientists (who study basic immunology) and clinicians (who test new approaches in patients).
Building a Foundation
With the infrastructure and collaborations in place to study cell therapy for cancer, Mackall says Stanford will be poised to be not only a leader in cell therapies for cancer, but other cell-based therapies as well.
“Giving someone living cells is completely different than giving someone a pill,” she says. “And if we make a commitment now to build a program that specializes in this, we’ll be in a great place to apply the approaches to a wide array of diseases in the coming years.”
The lab spaces, the understanding of how to engineer cells, the experience with genetic engineering and the familiarity with collaborating can all be easily adapted to these other burgeoning research areas as cell therapies take off.