HER2 CAR T Therapy Dramatically Improves Child’s Refractory Cancer

Killer T cells, green and red, surround a cancer cell, center. The T cells will attach and spread over the target, then use special chemicals housed in vesicles, red, to deliver the killing blow. Immunosuppresive lymphocytes interfere with the process. [National Institutes of Health]

One extremely frustrating aspect of cancer researcher and treatment is that some forms of cancer have no effective treatment options. Metastatic rhabdomyosarcoma, a form of muscle cancer that preferentially affects children, is an example of this type of intractable disorder. For the most part, metastatic rhabdomyosarcoma is mostly incurable, yet data from a new study from a team of investigators at Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital evaluated a novel immunotherapy option for cancer treatment on a child with rhabdomyosarcoma that had spread to the bone marrow. Amazingly, the researchers found no detectable cancer following treatment with chimeric antigen receptor (CAR) T cells that were engineered to target the HER2 protein on the surface of the cancer cells.

“This child’s cancer was considered high risk because it had not responded to standard chemotherapy,” explained lead study investigator Meenakshi Hegde, MD, assistant professor of pediatric hematology-oncology at Baylor College of Medicine and Texas Children’s. “As a result, this child was a candidate to receive a promising new CAR T cell therapy, a personalized form of immunotherapy that redirects the patient’s own immune T cells to recognize and fight the tumor.”

Findings from the new study were published recently in Nature Communications through an article titled, “Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma.”

Interestingly, about 75% of the tumor cells in this patient displayed a protein on their surface called HER2. The researchers reprogrammed the T cells to target the HER2 protein by genetically engineering them to express CAR molecules that recognize the HER2-expressing (HER2+) cancer cells.

https://www.cancer.gov/

In a previous clinical trial, the HEROS study, the Texas researchers found that CAR T cells directed at HER2+ tumor cells had a favorable safety profile. This early generation CAR T cell treatment resulted in clinical benefit in a small subset of patients, but it did not eradicate their tumors.

“From the HEROS trial, we learned that HER2-CAR T cells expanded but did not persist in the patients, which could in part explain the lack of anti-tumor responses,” said Hegde, who also is part of Baylor’s Dan L. Duncan Comprehensive Cancer Center.

To circumvent this limitation, the scientists added successive HER2-CAR T cell infusions along with low-dose chemotherapy to delete normal T cells as a strategy to improve the expansion and persistence of the infused HER2-CAR T cells in a trial they called, HEROS 2.0. The lymphodepletion chemotherapy administered before transferring HER2-CAR T cells eliminated the patient’s existing immune cells, creating a space for the engineered CAR T cells to expand in the patient.

“We analyzed the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells,” the authors wrote. “Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission, which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells.”

Hedge added that “although the child had a lasting response to HER2-CAR T cells with no tumor detected, the cancer returned six months after we stopped the T cell infusions. Fortunately, the child achieved a second remission after retreatment with HER2-CAR T cells. Considering the several challenges in successfully treating solid tumors using CAR T cells, achieving this exceptional tumor response is very encouraging.”

Amazingly, at the time of the publication, the child is 19 months off T cell treatment and remains healthy and cancer-free.

The sustained tumor response in this child has provided the researchers with valuable insights into how the cancer was eliminated. The CAR T cells were developed to recognize and attack HER2+ cancer cells. Although not all cancer cells expressed HER2 on the cell surface, the tumor was eliminated in its entirety, prompting the question of how the HER2-negative cancer cells were eradicated.

“We found evidence suggesting that, following the infusion of HER2-specific CAR T cells, the patient’s own immune system was recruited to act against the tumor, which might help explain the durable complete response,” Hegde said. “We plan on conducting more detailed experiments in a larger group of patients treated with HER2 CAR T cells to better understand the involvement of the patient’s immune system in eliminating the cancer.”

“It is fascinating to see remodeling of the patient’s T cell compartment and development of antibodies directed against proteins implicated in tumor survival and metastasis during the course of treatment in this child,” noted study co-author Sujith Joseph, PhD, a senior scientist at Baylor’s Center for Cell and Gene Therapy, who conducted the in-depth evaluation of the patient’s immune response. “The immune activation mechanisms and associated tumor targets unfolded during the acquired response, could inform novel approaches to fight difficult-to-treat cancers.”

Senior study investigator Nabil Ahmed, MD, an associate professor of pediatrics and immunology at Baylor and Texas Children’s Hospital, concluded that “this study shows that CAR T cells could perhaps act as vaccines by exposing cancer proteins to the patient’s immune system. With more understanding and further refinement of their design, CAR T cells could be effective against some incurable malignancies.”

Dott. Dario Sannino

Corporate Quality Sr. Manager at Bracco Imaging SpA.

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