In 2014, NewYork-Presbyterian and Columbia opened the doors of the Irving Bone Marrow Transplant Unit, a state-of-the-art facility for comprehensive bone marrow transplant (BMT) and cellular therapy care. Since then, the BMT and Cell Therapy Program has been at the forefront of therapies and research to help people with blood cancers, malignant and benign blood disorders, and autoimmune diseases and, to date, has treated more than 700 patients.
“The last 10 years have been transformative for our field,” says Markus Y. Mapara, MD, PhD, director of the Adult Blood and Marrow Transplantation Program at NewYork-Presbyterian and Columbia, who has led the unit from its inception. “Huge developments, from cellular immunotherapy to gene manipulation techniques, have really helped change the field.”
Below, Dr. Mapara discusses some of the major breakthroughs the program has helped pioneer over the past decade.
Advancing CAR-T Cell Therapy
Among the decade’s biggest medical developments is chimeric antigen receptor (CAR-T) cell therapy, a type of immunotherapy in which T cells are engineered to recognize and attack cancer cells. “CAR-T cell therapy has made it possible to offer cellular immunotherapy to patients with blood cancer, solid tumors, and even autoimmune diseases,” says Dr. Mapara. It has helped revolutionize treatment for two disease areas in particular: lymphomas and myeloma. Dr. Mapara says CAR-T cell therapy has been successful in treating a subset of lymphoma patients who have been unresponsive to standard treatment, while BCMA (B-cell maturation antigen) CAR-Ts have helped lead to long-term, progression-free survival for the myeloma population.
The cellular immunotherapy program at the Irving Bone Marrow Transplant Unit, led by Ran Reshef, MD, MSc, the unit’s director of translational research, is offering CAR-T cell therapy for adults with recurrent or persistent diffuse large B-cell lymphoma (DLBCL), a common form of non-Hodgkin lymphoma, and for patients with multiple myeloma. The program is working to expand the therapy to patients with solid tumors, as well as some autoimmune diseases and inflammatory conditions. So far, it has administered more than 130 CAR-T cell infusions and given 28 patients T-cell immunotherapy treatments.
NewYork-Presbyterian and Columbia also holds the distinction of being one of a small number of institutions equipped to grow and manipulate T cells for patients with cancer or severe infections, a role typically filled by pharmaceutical laboratories. In 2017, the institution established the Cellular Immunotherapy Laboratory, with Pawel Muranski, MD, as director, to produce clinical-grade immune cells under the FDA’s stringent Current Good Manufacturing Practice (cGMP) guidelines.
The cGMP facility is now producing antigen-specific T cells, under a treatment protocol developed by Dr. Muranski, to treat viral infections that either do not respond to standard viral medications or for which there are no antiviral drugs. This helps address a common problem in solid organ transplant and bone marrow transplant patients, explains Dr. Mapara. The protocol is approved by the FDA and patients have recently begun to be enrolled for treatment.
New cellular immunotherapy approaches are also in development; Dr. Mapara says one future goal is to manipulate T cells used for treating cancers so that they become resistant to immunosuppressive drugs in transplant patients.
The huge advantage of gene therapy is that you're dealing with a patient's own cells. You can’t overestimate the potential impact this approach will have on patients.
— Dr. Markus Mapara
Breakthrough Gene-editing Therapies for Sickle Cell Disease
As one of the country’s largest programs for stem cell transplantation for sickle cell disease, introduction of a novel treatment for this benign blood disorder represents a significant accomplishment. Dr. Mapara and his colleagues were involved in groundbreaking clinical research that led to FDA approval in 2023 of the first cell-based gene therapies for sickle cell disease.
“We were fortunate enough to be involved in the early wave of clinical trials that resulted in co-authoring four New England Journal of Medicine papers, published in the last three years, which focused on genetically engineering stem cells for two hemoglobinopathies: sickle cell disease and transfusion-dependent beta-thalassemia,” says Dr. Mapara.
CASGEVY, one of the FDA-approved therapies, is facilitated by the gene-editing technique known as CRISPR, in which a patient’s own stem cells are collected, edited, and reintroduced back into the body to help them produce fetal hemoglobin. This helps prevent red blood cells from sickling, ending the recurrent pain crises experienced so frequently by sickle cell disease patients. The second approved treatment, LYFGENIA, uses a lentiviral vector to genetically modify patients’ stem cells before reintroducing them back into the bloodstream to help produce an anti-sickling hemoglobin.
Dr. Mapara says the new therapies overcome a major barrier: the need for a stem cell donor. The standard of treatment for sickle cell disease has typically been a bone marrow or stem cell transplant from a matched donor, usually a sibling. “The huge advantage of gene therapy is that you're dealing with a patient's own cells. You don't have the rejection problems of either the donor cells attacking the recipient or the recipient rejecting the donor cells, which would lead to graft failure. You can’t overestimate the potential impact this approach will have on patients.”
Multidisciplinary Efforts to Improve Post-Transplant Tolerance
The complications associated with allogeneic transplants — such as rejection of the donor cells or graft-versus-host disease, in which transplanted donor immune cells attack the recipient’s tissues — are associated with increased morbidity and mortality for stem cell transplant patients.
However, allogeneic bone marrow and stem cell transplant does offer the opportunity to induce donor-specific tolerance, which can help overcome the need for lifelong immunosuppression for patients receiving solid organ grafts. The induction of donor-specific tolerance has been a focus for the BMT and Cell Therapy Program since its inception, and it collaborates with other departments across the institution on clinical research to bring new solutions to the forefront. This includes working closely with the Columbia Center for Translational Immunology and the Columbia Solid Organ Transplant Program to combine BMT and organ transplantation from the same donor for the induction of graft acceptance without the use of long-term immunosuppressant medication.
We are able to offer highly innovative protocols and treatments for patients. And the nice thing is that with all those new developments, new horizons open up.
— Dr. Markus Mapara
The treatment method is being tested through the ongoing PANORAMA clinical trial, led by NewYork-Presbyterian and Columbia transplant surgeon Joshua Weiner, MD. It explores the use of a human anti-CD2 antibody in combination with BMT to induce tolerance in living donor kidney transplantation. Last year, the multidisciplinary team performed four combined BMT and kidney transplants. “The primary endpoint for these studies is to be able to take patients off the drugs that they receive to suppress the immune system and not have the organ be rejected,” says Dr. Mapara. The trial is continuing to enroll patients and is expected to go on for the next few years.
Collaboration among NewYork-Presbyterian’s highly experienced specialists across a variety of disciplines helps set the program apart. “That is the benefit of having top-notch consulting colleagues at a large hospital, versus a specialized one,” Dr. Mapara says. “To successfully perform complex procedures such as combined organ and stem cell transplants or cell therapies for cancers, you need top experts in a variety of specialties. We work hand-in-hand with surgeons, nephrologists, and infectious disease doctors to provide the best possible care for our patients. This would not be possible at a place that does not have that breadth of expertise.”
A Look Ahead to the Next 10 Years
Dr. Mapara sees new directions for clinical care and research for the NewYork-Presbyterian and Columbia BMT and Cell Therapy Program as it enters its second decade. One objective is to replace the grueling, standard chemotherapy or irradiation-based conditioning that prepares BMT patients for stem cell transplantation with non-genotoxic approaches for patients who do not have underlying cancers. “There are potential antibody-mediated strategies that could be used without the damaging chemotherapy or radiation,” he says. “That could be a reality in the next five to 10 years.”
Dr. Mapara also expects to see cellular immunotherapies benefiting a larger swath of patients. “At the moment, transplant is still being used most of the time for cancer patients,” he says. “But with new tools in our hands, we will be able to broadly expand the application of these procedures for a large number of non-malignant diseases, including autoimmune diseases.”
Providing access to the most advanced therapies remains a top priority for the program. “We are able to offer highly innovative protocols and treatments for patients,” says Dr. Mapara. “And the nice thing is that with all those new developments, new horizons open up.”
