Collaboration eases the way for immunotherapies to move from lab to clinic

“Why?”

It is one of the first questions children learn to ask to understand the world around them. That single word has also powered incredible advances, such as our ancestors using what they knew about plant growth to create agriculture, or scientists questioning how electricity works, which led to understanding the physics that power our current digital world. The desire to know why also fuels progress in developing treatments for children with cancer: Why does one approach work when another does not? The St. Jude Center for Excellence in Pediatric Immuno-Oncology (CEPIO) brings clinicians and laboratory researchers together from numerous departments, including Immunology, Oncology, Surgery and Bone Marrow Transplantation & Cellular Therapy, to understand why and how these therapies work, to help usher in a new age of pediatric immunotherapies.

Immunotherapy harnesses a patient’s own immune cells to target and kill cancer cells. St. Jude was critical in developing a type of cellular immunotherapy called a Chimeric Antigen Receptor (CAR) T cell for B-cell acute lymphoblastic leukemia (B-ALL). While this approach has been very successful, CAR T–cell therapies for solid and brain tumors have yet to deliver similar clinical impacts despite promising laboratory research. CEPIO helps bridge the divide between laboratory findings and clinical results.

“We are constantly learning new things from each other,” said Stephen Gottschalk, MD, CEPIO co-director and Department of Bone Marrow Transplantation & Cellular Therapy chair. “CEPIO provides the infrastructure for fundamental immunotherapy research to be translated to the clinic, and for clinical samples to be brought to fundamental researchers to understand and improve clinical outcomes.”

CEPIO brings practical experience from the clinic to the lab

By putting laboratory scientists in the same room as physicians, CEPIO provides a place for ideas and practical experience to intersect. Lindsay Talbot, MD, Department of Surgery, who is a co-investigator on the 3CAR clinical trial for solid tumors and several other upcoming immunotherapy trials, helps shift how lab-based scientists think about the challenge of treating pediatric cancer.

“These tumors are hard, firm nodules, like rocks,” said Talbot. “It’s been enlightening for me to see that the fundamental biologists are surprised by that, because as a surgeon, I encounter it all the time. But I think that’s helped reframe for those scientists why this whole endeavor is challenging; we’re asking these T cells to invade a rock — of course it’s going to be hard to do.”

By combining this kind of practical knowledge with laboratory insights, CEPIO investigators are moving the next generation of CAR T–cell therapies into the clinic, including those targeting the cancer-related protein B7-H3, which have seen promising early results from 3CAR and its brain tumor sister study, Loc3CAR. Scientists are improving on the B7-H3 CAR T–cell therapy approach, having discovered that removing REGNASE-1 from the CAR T cells improved their performance, as published in Nature, and similarly, that deleting the gene DNMT3A may increase activity against solid tumors, as published in Science Translational Medicine.

CEPIO collaborators get CAR T cells safely to the brain

Getting a therapy to reach a brain tumor can be challenging, and understanding why it works or fails can be even harder. This is because, in some cases, surgery and collecting tumor samples are avoided for fear of damaging the brain. Similarly, any treatment to the brain can have serious risks, which are magnified in children whose brains are still developing. CEPIO brought together a multidisciplinary group to figure out how to use CAR T cells for pediatric central nervous system tumors.

Children treated for central nervous system tumors often have a catheter leading to the fluid surrounding the brain and spinal cord. Instead of giving CAR T cells through an IV, which would send them throughout the body, the scientists wondered if they could give the cells through the existing catheter, an approach other institutions were also exploring. CEPIO helped make such intracranial CAR T–cell infusions possible at St. Jude, with now well over a hundred given at the institution in just a few years.

“Before this, our neuro-oncologists had no experience in CAR T cells,” said Kelsey Bertrand, MD, MSc, MBBS, FAAP, Department of Oncology, who is a co-principal investigator on the Loc3CAR trial. “CEPIO brought us neuro-oncologists together with CAR T–cell and immunotherapy experts to get this trial up and running. We collaboratively addressed important aspects of the trial, from figuring out the manufacturing to predicting the likely unique side effects, and helping navigate the unexpected as it arose for this first-in-human approach.”

These partnerships also helped identify an opportunity in the guise of a challenge.

“With brain tumors and, to some extent, solid tumors, it is challenging to get a biopsy to see if CAR T cells are even getting into the tumor,” said Christopher DeRenzo, MD, MBA, Department of Bone Marrow Transplantation & Cellular Therapy, who is a co-principal investigator on 3CAR and Loc3CAR. “However, the catheter enables us to take samples at multiple time points after therapy. Studying those samples can give us insights into inflammatory signals over time, helping us understand why therapies do or don’t work and informing better next-generation immunotherapies.”

Understanding ‘why’ with reverse translation

Research findings that are ready to be used in patients are “translated” from the lab to the clinic. CEPIO supports an extra step of “reverse translation,” or correlative research on clinical cell-therapy studies, conducted at St. Jude through its Center of Translational Immunology and Immunotherapy (CeTI²). Through this approach, biopsies and other samples from clinical trials are brought back to the lab. Every cell therapy trial is designed with this step to help uncover molecular details and find out why and how they drive clinical results.

“We build correlative studies into our clinical trials to close the loop of translation,” said Rebecca Epperly, MD, Department of Bone Marrow Transplantation & Cellular Therapy, who is a co-principal investigator on 1922CAR for ALL, RAD3CAR for relapsed sarcoma and 3CAR. “We take samples from patients on the study, feeding them back to the lab-based investigators, and then that can help identify what the challenges and opportunities are to make each subsequent trial better for patients.”

Historically, improving treatments for childhood cancers has been stymied because it is difficult to assemble enough patients to perform clinical trials. CEPIO’s reverse translation approach is one way to address that challenge.

“It is truly humbling to see patients and families volunteer for these early phase trials, knowing sometimes it might now work for them, but that it could help the next child we treat,” said Swati Naik, MBBS, Department of Bone Marrow Transplantation & Cellular Therapy, who is a co-principal investigator on acute myeloid leukemia (AML) studies DIRECT70 and CATCHAML, as well as others for ALL. “Therefore, we have an obligation to ensure that we learn from each patient, which we do for every cell therapy trial at St. Jude.”

Through this approach, researchers have gained important insights. “One of the major things we’ve learned so far from these studies is that we can get our CAR T cells in the neighborhood of these solid tumors but can’t break through the doors of the cancer cells,” Epperly explained. “Now that we know that, we are already planning the next set of clinical trials to overcome these barriers.”

Making new CAR T–cell therapies with the Children’s Good Manufacturing Practice (GMP) facility

CEPIO is working hand-in-hand with the departments of Immunology, Oncology, Surgery and Bone Marrow Transplantation & Cellular Therapy and the on-campus Children’s Good Manufacturing Practice (GMP) facility to help accelerate the process of creating new cellular therapy products to test, keeping the lab-to-clinic-to-lab loop moving.

“Our principal investigators are never on their own,” said Frank Fazio, Children’s GMP, LLC president and St. Jude Therapeutics Production and Quality vice president. “We work with researchers to create scalable and repeatable processes that reach the requirements for Food and Drug Administration approvals to begin clinical trials.”

The Children’s GMP has experience in many areas, from protein production to cellular therapy manufacturing, giving St. Jude scientists a one-stop shop for translating their findings into clinical trials. Fazio’s team provides their expertise as collaborators, offering practical guidance while learning the nuances of a specific CAR T–cell design.

CEPIO is setting the foundation for advancing clinical pediatric immuno-oncology

With several clinical trials underway and many more planned, CEPIO investigators are charting new territory in the quest to treat pediatric cancer with immunotherapy. Novel fundamental research and reverse translation have ushered in a proliferation of preclinical studies. That work, fueled by asking and answering that burning question “why” question is laying the foundation for improving cancer care in an unprecedented way.

“CEPIO is a really unique immuno-oncology initiative that only exists at St. Jude,” said Hongbo Chi, PhD, CEPIO co-director and Department of Immunology chair. “Through it, multiple departments, specialties and expertise assemble together, from lab scientists to physicians to GMP professionals, all supporting each other to understand how these immunotherapies work, so we can collaborate with urgency to save more children with cancer.”