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Where Discovery Leads: Taking CAR T-Cell Therapy to Solid Tumors and Beyond

Published on
September 19, 2022
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“Emily

Emily Whitehead along side Stephan Grupp, MD, PhD.

By shafere1 [at] chop.edu (Emily Shafer)

Ten years ago, the field of pediatric cancer changed dramatically when the first child, Emily Whitehead, received chimeric antigen receptor (CAR) T-cell therapy for relapsed acute lymphoblastic leukemia (ALL) at Children's Hospital of Philadelphia. Her engineered T cells endured, and today she remains cancer free.

Thousands of pediatric patients around the world have since received CAR T-cell therapy for relapsed ALL, and researchers continue to study their cells to find ways to achieve a sustained response in even more patients.

After its success in treating ALL, CHOP physician-scientists are working diligently to harness the power of CAR T-cell therapy to treat other childhood cancers. CAR T-cell therapy works by programming the body's immune cells to kill cancer cells. In ALL, CAR T-cell therapy is designed to target CD19, the antigenic protein that is overexpressed by cancerous B cells.

While there is immense potential for CAR T-cell therapy in other childhood cancers, some cancers will be trickier than others, said Stephan Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section in the Division of Oncology, and director of the Cancer Immunotherapy Program at CHOP.

"Blood cancers like leukemia are present everywhere in the body, which is good from a CAR T perspective because there's nowhere that the leukemia cells can hide from the CAR T cells," said Dr. Grupp, who delivered the CAR T cells to Emily Whitehead. "Solid tumors are a tougher nut to crack, because tumors find ways of excluding T cells and preventing them from entering and killing the tumor."

Inspired and undaunted, researchers at CHOP are tackling brain tumors, neuroblastoma, and acute myelogenous leukemia, as well as finding ways to improve how CAR T delivery works in the body. Here are some of the inroads they're making with cellular therapy to improve outcomes for future patients, and in short videos, they share what excites them the most about their ongoing work.

Delivery to the Brain

Jessica Foster, MD, discusses the future if immunotherapy delivery. Access the video transcript

One of the challenges in translating CAR T-cell therapy's success in ALL to solid tumors lies in getting the T cells to the tumor — then making them stay there and stay active — said Jessica Foster, MD, attending physician in the Division of Oncology, who is studying delivery mechanisms for CAR-T therapy to reach brain tumors.

"Leukemia cells live in the bloodstream, which is where T cells normally live, so the CAR T cells can easily meet up with the cancer cells and kill them," Dr. Foster said. "The brain is a different beast because it is difficult to traffic the cells across the blood-brain barrier. We need to deliver the cells directly to the tumor while also sparing the healthy brain tissue."

One possible delivery mechanism of CAR T cells to the brain that Dr. Foster is evaluating is via the brain ventricles, which are cavities in the brain that produce and store the cerebrospinal fluid (CSF) that surrounds and cushions the brain. The advantage of using the brain ventricles is that they are easy to see and easily accessible using a small catheter.

Another method Dr. Foster is testing is injection into the cisterna magna, the largest of the CSF-filled subarachnoid cisterns, where the natural flow of fluid may help CAR T cells move directly into the brain.

Targeting brain tumors with CAR T cells poses the risk of negatively affecting normal brain tissue, particularly if the molecular target is also expressed by healthy tissue. Dr. Foster is researching the benefit of a transient CAR T-cell therapy that is made with mRNA, rather than viruses, to try and solve this conundrum

"The benefit of these transient CAR T cells is that there is a natural on-off switch. You can give the treatment in doses and withhold doses if it becomes toxic to the healthy brain," Dr. Foster said. "Certain tumors have an extra degree of risk because they are located in the middle of the brain. We hope transient CAR T cells will be especially beneficial for those patients."

Tackling Neuroblastoma

Another area of focus for CAR T cell research at CHOP is neuroblastoma, a tumor of nerve tissue that can occur in many areas of the body and most typically starts in adrenal gland tissues in the abdomen.

John Maris, MD, Giulio D'Angio Chair in Neuroblastoma Research, has dedicated his career to researching neuroblastoma. The Pediatric Cancer Dream Team, which is co-led by Dr. Maris, launched in 2013 with a $14.5 million grant co-funded by the St. Baldrick's Foundation and Stand Up To Cancer. The team's mission is to identify immunotherapeutic targets for hard-to-treat childhood cancers, including neuroblastoma.

"We were tasked with finding CD19-like molecules to target in neuroblastoma, and in the first four years of this grant, there was a brute force effort to discover new targets using genomics and proteomics," Dr. Maris said. "Since that time, we've been building immunotherapies in the labs."

This year, the first of what Dr. Maris hopes will be many clinical trials will open and begin testing a CAR T-cell treatment for neuroblastoma. The target is GPC2, an antigenic protein that is expressed on the surfaces of neuroblastoma and other solid tumors.

Another clinical trial set to launch in 2023 will utilize a different type of CAR called peptide-centric CARs. This type of CAR, created in the Maris Lab and described in the journal Nature, seeks proteins that are inside the cell, rather than on the surface. The CARs for this trial will target peptide derived from PHOX2B, a neuroblastoma dependency gene.

"We have multiple additional potential targets in the pipeline, both on the surface of the cells, and for the peptide-centric CARs," Dr. Maris said. "We really hope to make a major difference for our patients with other childhood cancers."

A More Human-like Antibody

Another active area of research is to determine why some patients' CAR T cells last for years, while others' CAR T cells last for less than a few months. CARs work by redirecting T cells to recognize the molecular target on cancer cells. The antibody proteins included in current CAR-T cell therapies are derived from mouse antibodies, which poses the risk of the human body recognizing the protein as foreign and rejecting the cells. Rejection may no longer be an issue thanks to research led by Shannon Maude, MD, PhD, attending physician at the Cancer Center.

"What we've done is altered the antibody to make it look more like a human protein by changing some of the DNA sequences," Dr. Maude said. "These humanized CAR T cells may help the T cells last longer and control disease better."

In a study that appeared in the Journal of Clinical Oncology, Dr. Maude and her team found that the humanized CAR T-cell therapy was safe and effective: 100% of patients with ALL who had not previously received CAR T-cell therapy experienced complete remission. Among patients who previously received CAR T-cell therapy, the overall response rate was 64%. More importantly, responses were durable in the majority of patients.

"The response rates and number of durable remissions were really promising," Dr. Maude said. We're hoping that the humanized CAR T-cell therapy can overcome this problem."

A Different Type of Leukemia

Sarah K. Tasian, MD, discusses the search for novel treatments for acute myeloid leukiemia. Access the video transcript

Sarah K Tasian, MD, chief of the Hematologic Malignancies Program at CHOP, associate professor of Pediatrics, and the Joshua Kahan Endowed Chair in Pediatric Leukemia Research, is always up for a good challenge.

She has taken on the difficult task of developing novel immunotherapies for children with acute myeloid leukemia (AML). AML is an aggressive blood cancer that requires intensive chemotherapy and often bone marrow transplantation. Many children with AML have a high risk of relapse and a poor prognosis.

"We are inspired by what we have seen in ALL using CAR T-cell therapy," Dr. Tasian said. "We want to harness a similar paradigm for AML, using immunotherapies, to try to overcome the chemotherapy resistance that contributes to AML relapse. However, this goal has been much harder given our difficulty in finding universal targets and the real risk of undesirable toxicity of these immunotherapies against normal healthy cells."

Two of the targets she and her colleagues identified in the lab have made their way to clinical trials. The first target is CD123, which is expressed on the cell surface of most pediatric AML cells. Based upon their work in the research lab and some clinical experience in adult patients, a pediatric-specific trial of an anti-CD123 CAR T-cell therapy is currently underway. A second pediatric phase 1 clinical trial is testing the activity of CAR T cells against CD33, another cell surface antigen that is expressed by AML cells.

The Tasian lab also is studying FLT3 as a target antigen for CAR T cell immunotherapy. FLT3 gene mutations occur in about 25% of children with AML and are associated with a high risk of relapse. One of the most exciting aspects of the FLT3 CAR T cells is that they not only appear to work against AML, but also very well against infant ALL, which has high levels of non-mutated FLT3 protein and frequent KMT2A gene rearrangements. Dr. Tasian and her team hope to open a FLT3 CAR T-cell therapy trial for children within the next two years.

"Everything we do is inspired by the problems that we see in our patients," Dr. Tasian said. "When a treatment fails patients, I work harder to fix that problem."