CHOP Remains on Cutting Edge of Cell and Gene Therapy

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Focus on High-risk Cancers

"These novel diagnostic, informatic, and treatment options will allow us to refine the treatment plan for each patient and learn from each patient to improve treatment for future patients."

While cancer remains the leading cause of disease-related death in children, precision medicine has emerged as a potentially transformative strategy for patients with high-risk cancers. With precision medicine, tumors are profiled to identify unique molecular alterations, and patients are offered therapy that specifically targets these vulnerabilities. Precision therapies can be effective across tumor types, redefining treatment based on a molecular target rather than histology. 

The Center for Precision Medicine for High-Risk Pediatric Cancer, a new Frontier Program, builds upon ongoing precision medicine efforts at Children’s Hospital of Philadelphia, bringing together specialists from across the hospital and Research Institute. Established as a “one stop” for children whose cancers lack an effective standard of care or relapse after initial therapy, the Center focuses on comprehensive multi-omics profiling of each patient’s tumor to define the best treatment options for that patient.

The Center leverages the work of three Centers of Emphasis: the Center for Single Cell Biology, the Center for Childhood Cancer Research, and the Center for Data-Driven Discovery in Biomedicine. Combined with the clinical tumor sequencing tools available within the Division of Genomic Diagnostics, this will enable the Frontier Program to build the largest dataset in pediatric cancer that combines information on the patient, tumor, multi-omics, epigenetics, and outcome.

“We will significantly expand our ability to conduct clinical trials, including novel studies based on CHOP laboratory discoveries, to rapidly translate these treatment options to patients,” said Theodore Laetsch, MD, director of the Center for Precision Medicine for High-Risk Pediatric Cancer. “These novel diagnostic, informatic, and treatment options will allow us to refine the treatment plan for each patient and learn from each patient to improve treatment for future patients.”

Therapy Benefit Persists Years Later

"The field has been waiting for the 5-year data, a key landmark in assessing long-term benefit and the potential for cure for some patients."

New data presented at the 2022 European Hematology Association Hybrid Congress highlighted the continued benefit of the first-ever approved CAR T-cell therapy, tisagenlecleucel (Kymriah), showing the treatment leads to durable remission and long-term survival five years post-treatment in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

“The field has been waiting for the 5-year data, a key landmark in assessing long-term benefit and the potential for cure for some patients,” said Stephan Grupp, MD, section chief of the Cellular Therapy and Transplant Section and inaugural director of the Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy at Children’s Hospital of Philadelphia. “These results mark a moment of profound hope for children, young adults, and their families with refractory B-cell ALL, as relapse after five years is rare.”

The findings coincide with the 10th anniversary of the first pediatric patient, Emily Whitehead, receiving this CAR T-cell therapy in a clinical trial at CHOP in a last effort to treat her relapsed acute lymphoblastic leukemia (ALL). Emily remains cancer free.

“What we learned from Emily has defined the entire field of CAR T-cell therapy,” said Dr. Grupp, who treated Emily. “We have since treated more than 440 patients at CHOP with this therapy, and thousands of pediatric patients around the world have received it as well. It has truly been a revolution in pediatric cancer care, and it started with Emily.”

FDA Approves Potential Curative Treatment

"This treatment is a potential game changer for patients who have required regular blood transfusions to manage their disease."

In 2022, the FDA approved beti-cel (Zynteglo), the first potentially curative therapy for patients who require regular red blood cell transfusions to treat beta thalassemia. Janet Kwiatkowski, MD, MSCE, director of the Thalassemia Center at Children’s Hospital of Philadelphia, was the lead investigator for the three clinical trials that led to the treatment’s approval. CHOP will be one of a few Qualified Treatment Centers that are offering the therapy manufactured by bluebird bio Inc.

Beta thalassemia is an inherited disorder that affects the production of normal hemoglobin. In the most severe form of the disease, patients are dependent on blood transfusions for life. The disease is caused by mutations on both copies of the hemoglobin beta chain gene. Beti-cel is a one-time gene therapy that adds functional copies of this gene to a patient’s own hematopoietic stem cells, which allows them to make normal to near normal levels of hemoglobin. In the three clinical trials, 89% of the patients who received the therapy were able to stop blood transfusions and maintain normal levels of hemoglobin.

This treatment is a potential game changer for patients who have required regular blood transfusions to manage their disease, an intense treatment burden that comes with its own risks,” Dr. Kwiatkowski said. “This FDA approval marks the fourth cell and gene therapy offered at CHOP, which has stood out as a pioneer in developing, studying, and administering these breakthrough therapies.”

‘Off the Shelf’ Allogeneic Cart

“This highly adaptable editing approach also has the potential for use to create ‘off-the-shelf’ CARs for other immunotherapy targets.”

Researchers at Children’s Hospital of Philadelphia collaborated with Beam Therapeutics to test and develop an “off the shelf” chimeric antigen receptor T cell (CART) using base editing, which allows for precise editing of the CART and less risk for negative outcomes that may accompany other editing methods. The CART, called 7CAR8, targets the surface receptor CD7, which is highly expressed on a vast majority of T-cell acute lymphoblastic leukemia (T-ALL) blasts.

In the setting of relapsed or refractory disease, T-ALL often does not respond to chemotherapy and chance of cure is low. The goal is for 7CAR8 to be an effective and life-saving therapy for these patients, if approved.

CAR T-cell therapy is typically created using a cancer patient’s own stem cells. But in this study, researchers tested an allogeneic CART made from healthy donors, which required modifications to prevent graft-versus-host-disease and CART rejection the patient’s immune cells. The modifications can be done using genome-editing, but this relies on DNA double-stranded breaks, which can cause unintended outcomes with potentially unforeseen consequences. To overcome this, the researchers used base editing to make single base pair changes. Base editing silences the gene expression without created double-stranded breaks.

The findings, published in the journal Blood, suggest 7CAR8 is highly active in preclinical models and, if approved, could potentially be a curative therapy for children and adults with relapsed or refractory T-ALL.

“Based on these results, we plan to translate 7CAR8 into the clinic for children and adults with relapsed or refractory T-ALL,” said senior author David Teachey, MD, director of Clinical Research in the Center for Childhood Cancer Research. “This highly adaptable editing approach also has the potential for use to create ‘off-the-shelf’ CARs for other immunotherapy targets.”

Potential Mechanism of Resistance Found

"... we will have the opportunity to study the molecular mechanisms of CD22 aberrant splicing and its abnormal protein isoforms, which could possibly be used as predictive biomarkers — and possibly even treatment targets — for new CD22-directed immunotherapies."

Despite the success CAR T-cell therapy has demonstrated in treating pediatric B-lymphoblastic leukemia (B-ALL), approximately 50% of patients relapse after the CD19-targeted therapy and move on to an immunotherapy that targets the CD22 protein. However, many patients relapse after this treatment, too.

Researchers at Children’s Hospital of Philadelphia found a potential mechanism of resistance to CD22-directed immunotherapy: aberrant splicing of the messenger RNA encoding CD22. This mis-splicing leads to downregulation of the CD22 antigen protein and makes malignant cells resistant to the CD22-directed immunotherapy. The findings appeared in Blood Cancer Discovery.

Led by Andrei Thomas-Tikhonenko, PhD, chief of the Division of Cancer Pathobiology, and Sarah K. Tasian, MD, chief of the Hematologic Malignancies Program, the research team analyzed RNA sequencing data of more than 200 B-ALL samples and compared it to data from healthy bone marrow donors. They identified numerous splicing variations in the B-ALL samples, including a novel isoform that skips CD22 exons 5 and 6, leading to the loss of part of the protein to which several antibodies and CARs attach.

“As CD22-directed immunotherapies emerge as potential frontline treatments for patients with B-ALL, we will have the opportunity to study the molecular mechanisms of CD22 aberrant splicing and its abnormal protein isoforms, which could possibly be used as predictive biomarkers — and possibly even treatment targets — for new CD22-directed immunotherapies,” Dr. Thomas-Tikhonenko said.

Targeting Unreachable Proteins

"Clearly, immunotherapy is underutilized for a lot of important reasons, and this approach will obviate some of the main obstacles to its success."

Researchers developed a new class of engineered T cells that target previously unreachable proteins inside cancer cells. The cells, called peptide-centric chimeric antigen receptor T cells (PC-CARs), led to the complete elimination of neuroblastoma tumors in a preclinical model, and are a turning point for treating solid tumors. The PC-CAR was developed by John Maris, MD, Giulio D’Angio Chair of Neuroblastoma Research, and Mark Yarmarkovich, PhD, an investigator in the Maris Lab.

CAR T-cell therapy has demonstrated tremendous success treating leukemia, but the same success has not translated to treating solid tumors, because while T cell targets for leukemia lie on the surface of cells, targets for solid tumors lie inside the nuclei of their cells. In this study, which appeared in Nature, the researchers focused on a peptide derived from the PHOX2B gene that has been implicated in hereditary neuroblastoma. They developed a PC-CAR that recognized this tumor-specific peptide across different HLA types. This approach is applicable to other genes for other solid tumors.

“I have watched many neuroblastoma patients die because of a lack of effective therapies, and this research is exciting because it is a potentially curative drug — and not just for neuroblastoma,” Dr. Maris said. “We’re sold on the power of this approach for other cancers. Clearly, immunotherapy is underutilized for a lot of important reasons, and this approach will obviate some of the main obstacles to its success.”

A group of CHOP researchers, including Dr. Maris, has joined a new Cancer Grand Challenges team that will receive $25 million to carry out team science. The CHOP team, Next Generation T cell Therapies for Childhood Cancers (NextGen), also includes Dr. Yarmarkovich, Patrick Grohar, MD, PhD, director of translational research in the Center for Childhood Cancer Research, and Nikoloas Sgourakis, PhD, associate professor in the Center for Computational and Genomic Medicine. The team will take on the Solid Tumours in Children Challenge, to develop novel therapies targeting solid tumors in children.