Center of Excellence in Pediatric Immuno-Oncology fast-tracks progress from the lab to the clinic

Over a century ago, physician-scientist William Coley pioneered the first formally documented immunotherapy by stimulating the immune system with an infectious agent to treat cancer. While Coley suspected his treatment exploited an interaction between a patient’s immune system and their cancer, he did not know enough about the immune system in the 1890s and early 1900s to explain why the approach worked. That lack of understanding led the medical community to abandon his ideas for decades. 

Time has vindicated Coley, “The Father of Cancer Immunotherapy.” More modern forms of the treatment have demonstrated remarkable clinical success by curing multiple types of cancer, leading to Food and Drug Administration (FDA) approval for several immunotherapeutics and the 2018 Nobel Prize in Physiology or Medicine. However, immunotherapy has not been as successful for other cancer types, including pediatric solid or brain tumors, suggesting that there is more to discover about the underlying immuno-oncology.

Coley’s example shows that strong communication between clinical scientists and fundamental biologists is necessary to move forward innovative cancer treatment ideas. These groups must interact with each other directly, sharing feedback and knowledge. St. Jude recently created the Center of Excellence for Pediatric Immuno-Oncology (CEPIO) to provide a forum for researchers across the immuno-oncology spectrum, from laboratory science to those working directly with patients.

“We’ve established CEPIO to help foster an open, collaborative culture between those studying fundamental immunology and those working in clinical translation,” said Hongbo Chi, PhD, CEPIO co-director and St. Jude Department of Immunology chair.

“Our shared goal at St. Jude is to cure pediatric malignancies,” echoed Stephen Gottschalk, MD, CEPIO co-director and St. Jude Department of Bone Marrow Transplantation & Cellular Therapy chair. “CEPIO will facilitate that by bringing investigators together and providing funds to go from the lab into clinical translation, and from the clinic back into the lab.”

The organization revolves around three comprehensive research areas within immuno-oncology that reinforce each other: systems immunology, functional genomics and translational immuno-oncology.

Improving immuno-oncology through fundamentals

“One main discovery arm of CEPIO, systems immunology, uses tools such as single-cell RNA sequencing, network analysis, hidden driver prediction and other data-driven approaches,” Chi said. “With these cuttinge-edge technologies, we can profile and analyze pediatric cancer samples and preclinical models to better understand the tumor immune landscape.”

One ongoing problem for immunotherapies is the unexpected ways tumors interact with their local environment in the body, and how that impacts treatment. For chimeric antigen receptor (CAR) T cells, immune cells collected from a patient and reprogrammed to target cancer cells, there have been continued challenges in treating solid tumors as they often become treatment resistant.

“Part of what we want to understand are the basic mechanisms of immune resistance,” Gottschalk said. “For example, why do T cells get exhausted or lose their effectiveness within tumors? We must first understand that fundamental biology to create strategies to overcome these problems.”

St. Jude researchers are capitalizing on the power of systems immunology to address these issues highlighted by three examples below: 

• In a recent Cancer Discovery publication, co-corresponding authors Jiyang Yu, PhD, Department of Computational Biology interim chair and Terrence Geiger, MD, PhD, Academic and Biomedical Operations senior vice president and Department of Pathology member, and co-author Chi, showed that tumors with low GPR65 expression recruit immunosuppressive cells that suppress the local immune response, including CAR T-cell function, but those signals can be modified to improve therapy.
• Published in Nature, Chi’s lab detailed how tumors and cancer-killing immune cells compete over the nutrient glutamine and how supplementing with extra glutamine significantly increased anticancer activity, overcoming immunosuppression in the tumor microenvironment.
• Gottschalk and Jinghui Zhang, PhD, St. Jude Department of Computational Biology member, used a computational approach with in vivo validation to identify 156 potential targets in solid and brain tumors for CAR T cells, as published in Nature Communications.

Systems biology at St. Jude is already unveiling the complex interactions between a tumor, its microenvironment and immune regulatory networks, and CEPIO promises to accelerate those discoveries.

Discovering the causal drivers to bolster immunotherapy

CEPIO’s second discovery arm focuses on functional genomics. Chi’s group has been applying CRISPR-mediated gene-editing technology to find which genes are essential to immune cell function, such as those critical for CAR T cells, and which tumor genes are essential for cancer survival or resistance to immunotherapy.

“CRISPR screens are a powerful way to identify functionally relevant targets or causal drivers in an unbiased way,” Chi explained. “Through these high-dimensional genetic perturbations, we can identify causal relationships, not just correlative relationships. That enables us to identify new cancer driver genes whose targeting enables effective immunotherapy.”

These screens have already shown promise:

• Chi and Gottschalk found a protein in cancer cell’s mitochondria that acts as a ‘signal jammer’, antitumor immune function. This provides a new therapeutic target to improve immunotherapy, as published in Nature.
• Chi’s lab mapped the transcription factor network that drives T cells from precursors to intermediate states to their final exhausted status. Also published in Nature, the work identifies potential ways to drive cells towards effector states and prevent exhaustion.

Connecting immuno-oncology to the clinic through cellular and genetic engineering

“Our hope on the translational side is that CEPIO will facilitate preclinical and early clinical testing,” Gottschalk stated. “The Center provides a forum for us to learn about the most promising work in the discovery arms, such as the gene targets identified by Dr. Chi, which should facilitate rapid translation of those findings into early-phase clinical trials.”

“As a basic researcher, seeing my group’s discoveries starting to move to the clinic so quickly is truly rewarding,” Chi said. His lab originally identified that targeting REGNASE-1 markedly improves T-cell antitumor function, a collaborative effort with Geiger published in Nature that is now moving toward the clinic.

Historically, clinical research lags far behind discoveries in the lab, sometimes by decades. Regular contact between immuno-oncology experts in CEPIO is designed to cut that delay down as much as possible. The translational arm is tasked with translating discoveries into preclinical models and clinical trials. This includes overcoming practical hurdles in bringing these findings into clinical use, such as optimizing cellular and genetic engineering strategies. 

Examples of current and ongoing cellular and genetic engineering approaches are:

• Collaborators Giedre Krenciute, PhD, Cailtin Zebley, MD, PhD, both of the Department of Bone Marrow Transplantation & Cellular Therapy, Benjamin Youngblood, PhD, Department of Immunology, and Gottschalk discovered that removing the gene DNMT3A from CAR T cells universally reinvigorates the immune cells across solid tumor types where CAR T-cell therapy has not been successful. The study was published in Science Translational Medicine.
• As published in Cell Reports Medicine, Paulina Velasquez, MD, Department of Bone Marrow Transplantation & Cellular Therapy, M. Madan Babu, PhD, FRS, St. Jude Senior Vice President of Data Science, Chief Data Scientist, Center of Excellence for Data-Driven Discovery director, and Department of Structural Biology member, Jeff Klco, MD, PhD, Department of Pathology, Krenciute and Gottschalk showed that they could use structural modeling to inform the design of bispecific CAR constructs for acute myeloid leukemia (AML).
• Gottschalk, Krenciute and Lindsay Talbot, MD, Department of Surgery, created a novel CAR construct that contains an anchor to create larger signaling complexes to improve the antitumor efficacy not only of CAR T cells but also other immune cells such as natural killer cells, as reported in Nature Biotechnology.

In parallel to these efforts, the translational arm also provides the opportunity for reverse translation, where patient samples and associated treatment outcomes are collected from active clinical studies and given to fundamental immunologists. This process creates a positive feedback loop, where understanding of immuno-oncology pushes forward clinical immunotherapy, then vice versa, until these treatments deliver on their promise for children with cancer.

“CEPIO is here to help St. Jude immuno-oncologists move fundamental insights from the bench into the clinic and back,” Gottschalk concluded. “Through that iterative process, we will get one step closer to reaching our collective goal of learning how to destroy all cancer cells, so that all children diagnosed with cancer can be successfully treated and return to their normal lives.”

With CEPIO, these scientists can finish what Coley started, by communicating their findings effectively and supporting each other. This community will work together to stay at the forefront of immuno-oncology and its translation into better clinical outcomes for pediatric cancer.