In a clinical trial evaluating a novel immunotherapy option for cancer treatment, a child with rhabdomyosarcoma, a form of muscle cancer, that had spread to the bone marrow, showed 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.
The trial, conducted by researchers at Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, USA, was recently published in the journal Nature Communications.
“This child’s cancer was considered high risk because it had not responded to standard chemotherapy. As a result, this child was a candidate to receive a promising new CAR T cell therapy, a personalised form of immunotherapy that redirects the patient’s own immune T cells to recognise and fight the tumour,” said first and corresponding author Dr. Meenakshi Hegde, assistant professor of paediatric haematology-oncology at Baylor College of Medicine and Texas Children’s.
About 75 percent of the tumour 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 recognise the HER2-expressing (HER2 ) cancer cells.
In a previous clinical trial, the HEROS study, the researchers found that CAR T cells directed at HER2 tumour cells had a favourable 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 tumours.
“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-tumour responses,” said Hegde, who also is part of Baylor’s Dan L Duncan Comprehensive Cancer Center.
To overcome this limitation, Hegde and her colleagues 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 lymphodepleting 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.
“Although the child had a lasting response to HER2-CAR T cells with no tumour 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,” Hegde said. “Considering the several challenges in successfully treating solid tumours using CAR T cells, achieving this exceptional tumour response is very encouraging.”
At the time of this report, the child is 19 months off T cell treatment and remains healthy and cancer free.
The sustained tumour response in this child has provided the researchers important insights into how the cancer was eliminated.
The CAR T cells were developed to recognise and attack HER2 cancer cells.
Although not all cancer cells expressed HER2 on the cell surface, the tumour 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 tumour, 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 remodelling of the patient’s T cell compartment and development of antibodies directed against proteins implicated in tumour survival and metastasis during the course of treatment in this child. The immune activation mechanisms and associated tumour targets unfolded during the acquired response, could inform novel approaches to fight difficult-to-treat cancers,” said Dr. Sujith Joseph, senior scientist at Baylor’s Center for Cell and Gene Therapy, who conducted the in depth evaluation of the patient’s immune response.
“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,” said senior author Dr. Nabil Ahmed, associate professor of paediatrics and immunology at Baylor and Texas Children’s Hospital.
Source: Baylor College of Medicine