by Molly Chiu, Baylor College of Medicine

Credit: Pixabay/CC0 Public Domain

Researchers at the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital have developed a chimeric antigen receptor (CAR) T-cell therapy targeting T-cell lymphoma, an aggressive and difficult-to-treat cancer.

A first-in-human phase I clinical trial of patients with relapsed or refractory T-cell lymphoma found early signals of anti-tumor efficacy and safety. The results are published in the journal Blood Journal.

All patients in the trial were treated extensively with other therapies prior to treatment with the investigational CAR T cells. Clinical responses were observed in four out of nine patients (44%), with two patients achieving complete responses. A third patient had an initial mixed response, received a second infusion of CAR T cells, and proceeded to allogeneic hematopoietic stem cell transplantation.

The patient is currently in remission, almost five years after CAR T cell treatment. A fourth patient had a partial response. There were no severe side effects, and the most common side effect, cytopenias, was mostly self-resolved.

"These findings are very encouraging. We have shown that it is feasible to target T cell malignancy with CAR T cell therapy. This treatment has a very good safety profile with few severe toxicities. Patients are able to receive the therapy in the outpatient setting, and they don't feel very sick as a result of treatment," said Dr. LaQuisa Hill, first author of the study and associate professor at the Center for Cell and Gene Therapy. Hill also is a member of Baylor's Dan L Duncan Comprehensive Cancer Center.

Patients with relapsed or refractory T cell lymphoma or leukemia have a poor prognosis because currently available therapies often are not effective long-term. CAR T cell therapies have shown remarkable efficacy in B cell malignancies, with six CAR-T products now commercially available, but none have been approved in T cell malignancies.

"Developing a CAR T cell therapy for T cell lymphomas has been challenging because the same engineered receptors that recognize the tumor can also target normal T-cells," said Dr. Maksim Mamonkin, senior author of the study, associate professor in the Center for Cell and Gene Therapy and member of the Dan L Duncan Comprehensive Cancer Center at Baylor.

"That increases the risk of CAR T cells killing each other before they see the cancer cells. There's also a possibility these CAR T cells will deplete the normal T cells circulating in the body, creating dangerous immunosuppression. Both of these limitations were overcome with our targeting approach."

The CAR T cell therapy in this phase I trial uses the patient's own T cells, modified in the lab to target the CD5 protein, which is highly expressed in T cell lymphoma and in normal T cells. In preclinical studies, researchers found that the CD5-specific CAR T cells did not eliminate themselves due to the rapid degradation of CD5 protein, making CAR T cells invisible to each other and free to target tumors.

"We have only seen this outcome when targeting CD5, but not with any other antigen," Mamonkin said. "This finding in the laboratory was accidental, and it turned out to be very serendipitous."

Researchers modified the manufacturing process during the trial based on patients' results. They shortened the manufacturing time for the CAR T cells, increasing the therapy's potency. Patients who responded to treatment were all treated with CAR T cells made with the modified manufacturing process.

"We have found a straightforward way to generate CD5 CAR T cells without additional engineering while producing the most benefit in patients without effective therapy options," Mamonkin said.

The therapy has been licensed to March Biosciences and will be evaluated in a larger multicenter phase II trial to be opened in the second half of 2024. Meanwhile, the phase I trial will remain open and is still recruiting patients.

"We encourage patients to enroll as early in their treatment as possible after failure of one to two lines of therapy," Hill said. "We know that the more chemotherapy patients receive, the lower the quality of their T cells. If patients are treated earlier in the disease course, both patients and their T cells will be 'more fit,' which may further improve outcomes."

More information: LaQuisa C. Hill et al, Anti-tumor Efficacy and Safety of Unedited Autologous CD5.CAR T cells in Relapsed/Refractory Mature T-cell Lymphomas, Blood Journal (2023). DOI: 10.1182/blood.2023022204

Journal information: Blood 

Provided by Baylor College of Medicine 

Metastatic cancer patients more likely to survive at academic and high-volume hospitals when given immunotherapy: Study

by Yale School of Medicine

Credit: CC0 Public Domain

A new study led by Yale Cancer Center researchers at Yale School of Medicine has revealed a significant increase in patients starting immunotherapy within one month of death. Using a national clinical database, the researchers focused on patients with metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). They were treated with immune checkpoint inhibitors from the point of FDA approval, through to 2019. The melanoma cohort began treatment in 2012 and the RCC and NSCLC cohorts in 2016.

The findings were published in JAMA Oncology on January 4.

"Immunotherapy has revolutionized the field of oncology over the last decade," said Sajid Khan, MD, senior author of the study and section chief of Hepato-Pancreato-Biliary (HPB) and Mixed Tumors at Yale School of Medicine. "Because survival is substantially improved for many patients treated with these drugs, its application has increased across the United States. In our study, we focused on immunotherapy initiation at the end of a patient's life with cancer metastasis."

Because the therapy is relatively new, the study aimed to "offer insights into national prescribing patterns and serve as a harbinger of shifts in the clinical approach to patients with advanced cancer."

The study included 20,415 stage IV melanoma patients, 197,331 stage IV NSCLC patients, and 24,625 stage IV RCC patients. Researchers considered each patient's age, sex, race, and ethnicity as well as the location of metastases and the medical facility where treatment was given.

"We were interested in gauging how frequently immunotherapy is initiated within the last 30 days of life," said Khan, a member of Yale Cancer Center and the co-director of Team Science at Yale Center for Clinical Investigation. "Our study found that the initiation of immunotherapy in the last month of a patient's life has significantly increased in the last 10 years, accounting for one in 14 immunotherapy treatments overall."

For patients with metastatic melanoma, the increase was from 0.8% to 4.3%, for NSCLC 0.9% to 3.2%, and for RCC 0.5% to 2.6%. In 2019, these end-of-life-initiated (EOL-I) treatments represented 7.3% of all immunotherapy treatments, indicating a growing application of EOL-I immunotherapy.

Where patients were treated with immunotherapy mattered. "There were improved survival outcomes when the therapy was administered at academic and high-volume facilities," said Khan. While patients treated at non-academic or low-volume hospitals had higher odds of receiving EOL-I immunotherapy, patients were less likely to experience death at academic and high-volume hospitals when given immunotherapy for metastatic cancers.

"Another noteworthy finding was that the outcome for patients receiving immunotherapy towards the end of their life was different depending on the burden of metastasis. Patients with more than three sites of distant metastases are more likely to die within one month of immunotherapy initiation than those with only distant lymph node metastasis."

The researchers note that immunotherapy provides a strong overall survival benefit and can salvage patients with metastasis, even those in high-risk sub-groups. The study findings highlight the need for further investigation into the implications of EOL-I immunotherapy with the hope of refining treatment guidelines for the benefit of patients facing metastatic cancer.

Daniel Kerekes from Yale School of Medicine and Yale Department of Surgery was the study's first author. Alexander Frey, Elizabeth Prsic, Thuy Tran, James Clune, Mario Sznol, Harriet Kluger, Howard Forman, Robert Becher, and Kelly Olino were Yale co-authors.

More information: Daniel M. Kerekes et al, Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US, JAMA Oncology (2024). DOI: 10.1001/jamaoncol.2023.6025

Journal information: JAMA Oncology 

Provided by Yale School of Medicine