Manufacturing Hope:

Pathology’s Transfusion Medicine Team Helps Bring Cutting-Edge
T-Cell Immunotherapy to Montefiore Patients

Montefiore recently became the first site in the United States to be approved for the use of TECARTUS (brexucabtagene autoleucel) CAR-T cell therapy -- the first and only chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory Mantle Cell Lymphoma (MCL). 

An aggressive, rare B-cell non-Hodgkin lymphoma, MCL affects approximately one in 200,000 Americans each year. It’s more common in men, with a median age range at diagnosis of 60 to 70 years old. The survival rate is poor. 

Montefiore’s Hematologic Malignancy and Transplant team, led by Ira Braunschweig, MD, was chosen to treat the first patient based on their proven expertise in cellular therapy and leadership in CAR-T therapy. Dr. Braunschweig was an Investigator for the ZUMA-1 study to test CAR T-cell therapy for relapsed refractory lymphoma. The subsequent ZUMA-2 study showed a nearly 90-percent response rate in patients, establishing CAR-T therapy as the standard of care for patients in whom other therapies have failed. 

Vital in the ZUMA-1 study, and in ongoing work by Dr. Braunschweig and his team involving Kite’s CAR-T cell therapy, is their collaboration with the Montefiore Einstein Pathology Department’s Apheresis Clinic, directed by Monika Paroder, MD, PhD, and its Cellular Therapy Laboratory, directed by Randin C. Nelson, MD. Both units are operated by the department’s division of Transfusion Medicine, under the direction of Joan Uehlinger, MD. 

Dr. Nelson and Dr. Paroder discuss their teams’ contributions in helping bring this cutting-edge cancer therapy to Montefiore patients. 

Who are your team members and what is your team’s role in the TECARTUS project?
Dr. Nelson: Manufactured by Kite Pharma, Tecartus CAR-T is an FDA-approved, CD19-directed, genetically modified autologous T cell immunotherapy. Our Apheresis Clinic and Cellular Therapy Laboratory act as approved manufacturing partners with Kite Pharma.

The key team members from Pathology include myself and Dr. Paroder, assisted by our wonderful laboratory technologist and nursing staff led by Carlo Palesi, CLS, Cellular Therapy Laboratory Manager, and Angie Bonzon-Adelson, RN, Apheresis Nurse Manager. The medical team also include Jamal H. Carter, MD, and James M. Szymanski, MD, Associate Directors of Transfusion Medicine, both of whom are trained in Blood Banking / Transfusion Medicine and in Anatomic and Clinical Pathology.

How did you collaborate with the Oncology team?
Dr. Nelson: The Apheresis Clinic and the Cellular Therapy Lab have collaborated with the bone- marrow transplant services of both pediatric and adult oncology for many years. We perform collection, processing, and cryopreservation of stem cells for Montefiore patients needing stem cell transplantation—we collect and process stem cells for over 150 patients annually.

We’ve been collaborating with oncology for novel cellular therapy trials since late 2015, when Montefiore joined the ZUMA-1 trial, which led to FDA approval of Kite’s first cellular therapy Yescarta (axicabtagene ciloleucel) which is used to treat diffuse large B-cell lymphoma. We’ve treated over 30 Montefiore patients with Yescarta in partnership with Kite and the adult transplantation service led by Dr. Braunschweig. We also have a biweekly Cellular Therapy Working Group who meet to discuss novel cellular therapies and strategize which therapies may have the biggest benefit to our patients at Montefiore.

What is your team’s role in the “manufacturing” process?
Dr. Nelson: The FDA considers our role in the process part of the “manufacturing” of this FDA-approved cellular therapy treatment. While what we do is very different from a manufacturer producing a traditional pill or IV drug, we’re subject to the same regulations. Thus, there’s a large responsibility to develop procedures and maintain equipment and facilities such that they are compliant, as well as the burden of record-keeping to ensure that all of these requirements are met and documented.

Dr. Paroder: The procurement of the patient’s T cells, which will then be manipulated to produce CAR-T cells, is the first and rate-limiting step in the manufacture of any cellular therapy product. This is done via apheresis, a technique used to separate blood into components -- namely plasma, red blood cells and white blood cells -- allowing us to isolate the component we want to remove (in the case of CART therapies it’s the white-blood-cell layer). Our highly skilled apheresis nursing team performs these cellular collections. The cells we collect are then engineered and used to make the cellular therapies that are providing remissions and cures for previously intractable malignancies.

What challenges do you face in carrying out your role?
Dr. Nelson: Most cell therapy trials we bring online require months of planning and training. The most intensive part of which is vetting by Kite (or another sponsor) to confirm our practices in both the Apheresis Clinic and the Cellular Therapy Lab meet their high standards to partner with them in creating these cutting-edge therapies. This is not a one-time thing; there are also annual audits. So in any given year, our facilities and staff are subject to inspections by the FDA, the College of American Pathologists (CAP), Foundation for the Accreditation of Cellular Therapy (FACT), and New York State inspections as well as audits by the numerous cellular therapy companies that we have partnered with. Additionally, staff training of nursing and lab technologists is required for each unique product.

Once all of that is together, the actual handling of the product is quite straightforward, as it’s often very similar to the process the clinic and lab have used for stem cell transplantation for decades. In the case of Tecartus, we had a much quicker turnaround to get things up and running, because we already have been vetted by Kite for their Yescarta product.

Dr. Paroder: As Dr. Nelson mentioned, any cellular therapy trial we bring to Montefiore requires very precise planning, training of staff, working out processes to make sure the workflow is optimized and making sure we conform to the required standards and various regulations, not just at initiation of a trial but consistently. Ultimately, as with all other therapeutic procedures we perform here, we need to make sure these procedures are performed at the highest standard, safely and efficiently. We’re involved in collections for numerous cellular products here at Montefiore, with Tecartus recently being added to the list.

How long does it typically take to harvest the T cells from a patient? What special procedures are required?
Dr. Nelson: The patient’s mononuclear cells are collected by the skilled nurses of our clinic using apheresis technology. The apheresis instrument centrifugally separates the patient’s blood into layers, and the mononuclear cell layer (containing the T cells) can be collected, while the plasma, red blood cells, and platelets are returned to the patient’s body. The procedure takes 3 to 4 hours. To process this much of the patient’s blood so rapidly usually requires central venous access with a large-bore, rigid catheter that’s typically placed by the Interventional Radiology service. After the collection, the patient’s cells are sent to Kite for processing into CAR-T cells.

How long did it take to get cells back from Kite to be re-infused into the first patient?
Dr. Nelson: The manufacture of the product takes 2 to 3 weeks. In the case of our first patient, the patient’s genetically modified autologous T cells (Tecartus) were infused only 19 days after the cells were collected in the Apheresis Clinic.

What have been the results of the therapy in this first case, so far?
Dr. Nelson: The patient tolerated the infusion, and experienced a number of symptoms which can correlate with good clinical response—therefore we are hopeful. It is still too early, however, to be able to judge his response.

Has your lab played a role in the other CAR-T therapies currently in use at Montefiore?
Dr. Nelson: Yes. All CAR-T and other cellular therapy products at Montefiore come through our Cellular Therapy Lab. The lab is licensed as a Tissue Bank by the New York State Department of Health, and is accredited by FACT. Frequently, the Cell Therapy Collection Service, directed by Dr. Paroder, is also involved, as the majority of these products are manufactured from the patient’s own cells, which are typically collected by apheresis.

Are you and your team involved in any other clinical trials involving Car-T therapy or therapies for any other diseases?
Dr. Nelson: Yes. We currently support more than 10 novel cell therapy products (many of which are in the clinical trial phase) for pediatric and adult oncology. This includes therapies for multiple myeloma, various types of lymphoma, and sarcoma.

As Pathologists, you typically work behind the scenes helping clinical colleagues deliver the best possible patient care. You’ve discussed the challenges inherent in TECARTUS and related projects. In what ways do you find this work rewarding?
Dr. Nelson: In the Apheresis Clinic and Cellular Therapy Lab we know that, without our efforts, these treatments simply wouldn’t be available to patients at Montefiore. To know that we help to make these cutting-edge therapies for patients available to the people of the Bronx, is extremely rewarding.

Dr. Paroder: Cancer immunotherapy is a tremendous breakthrough in cancer care and it’s incredibly exciting and rewarding to help actually deliver these therapies to patients. Nothing can happen without apheresis – it’s the first step in the process.

Adoptive cell transfer (which includes CAR-T cells) is a rapidly evolving and growing form of cancer immunotherapy harnessing the body’s own immune cells to fight cancer. Previously restricted only to clinical trial settings, FDA approval of two CAR-T therapies in 2017 opened the door to using these agents much more “routinely.” The number of clinical trials being conducted and available cellular therapies becoming available for diseases that were previously essentially untreateable is really remarkable.

Collaborations and combined efforts of the academic, clinical, and pharmaceutical sectors is absolutely necessary to bring these breakthrough therapies to patients. This is an incredibly exciting time for the field. Researchers are pushing the boundaries of what can be done with these “living drugs,” working to bring patients effective, personalized, safe and optimized cellular products. I’m hopeful that their use can be extended beyond hematologic malignancies in the near future to provide possible options for patients.

Cellular Laboratory Team

Montefiore Einstein Pathology, Transfusion Medicine, Cellular Laboratory Team
From left: Randin Nelson, MD, Director; Johanna Rojas, MBA, MLS (ASCP)CM, Supervisor; Sharon James, MBA, Technologist; Carlo Palesi, CLS, Manager.

Transfusion Medicine Leadership

Montefiore Einstein Pathology, Transfusion Medicine Leadership
From left: Monika Paroder, MD, PhD, Director, Apheresis Clinic; Joan Uehlinger, MD, Director, Transfusion Medicine and Blood Banking Division; Jamal Carter, MD, Associate Director, Transfusion Medicine. Not pictured: Randin Nelson, MD; James Szymanski, MD, Associate Director, Transfusion Medicine

Apheresis Clinic

Montefiore Einstein Pathology, Transfusion Medicine, Apheresis Clinic
Apheresis Technologist and Nursing Team, from left: Ancy Kurian, RN; Angie Bonzon-Adelson, RN, Nurse Manager; Sunu George, RN; Pearl Webster, RN; and Angie Uytiepo, RN.