I am one of the investigators in the phase I, open-label, dose-escalation trial with ADP-A2M4 designed to evaluate the safety, tolerability, and anti-tumor activity in certain patients with solid tumors. At the recent European Society for Medical Oncology (ESMO) Congress, I presented updated findings from 12 patients with synovial sarcoma, which demonstrated that ADP-A2M4, a T-cell therapy targeting the MAGE-A4 antigen, had a clinical response rate of 58 percent. As synovial sarcoma is one of the rarest types of cancers with limited treatment options, this research is very meaningful for patients battling the deadly cancer.
Road to Sarcoma Treatment
Synovial sarcoma is a soft tissue sarcoma, which represents less than 1 percent of all malignant tumors and synovial sarcoma is even more uncommon. About 800 new cases of synovial sarcoma are diagnosed in the U.S. each year, with most diagnoses striking patients under 30 years old and in the prime of their lives. The overall 5-year survival rate for synovial sarcoma is 36-76 percent; however, each patient's experience is different. The survival rate for synovial sarcoma is lower in cases where the cancer has returned or spread. The current standard of care for synovial sarcoma includes chemotherapy, oral agents, and a lot of off-label use.
I received my Bachelor of Science degree from the Departments of Chemistry and Biochemistry at The University of Arizona in 1995. I completed my MD and PhD degrees at the University of Alabama at Birmingham in 2005 with my PhD background in cervical and breast cancer research. I then came to Washington University in St. Louis/Barnes-Jewish Hospital, where I did my Internal Medicine Residency and Medical Oncology Fellowship.
I decided to focus on sarcoma during my clinical fellowship after I met the first of my patients with this dreadful disease: a young woman diagnosed with rhabdomyosarcoma on her heart, who was 22 weeks pregnant. I became aware that there were so many unmet needs, including clinical, for sarcoma patients like her. Since then, I have not looked back and I learn from every patient I meet and treat.
Researchers began exploring new ways, such as cell therapy, of treating this type of cancer revealing that more than 90 percent of synovial sarcoma show specific translocation t(X:18) involving SYT and SSX genes. SYT and SSX and the abnormal fusion (chimeric) protein (SYT-SSX) represent tumor-specific abnormal molecules and are ideal targets for drug therapy and vaccine/immunotherapy.
The Promise of Immunotherapy
Immunotherapy utilizes the immune system by modifying immune cells to help enhance their ability to target and destroy cancer. The research I presented at the 2019 ESMO Annual Congress was conducted with T-cell therapy that modifies specialized white blood cells, called T cells, so they can better attack cancer. These T cells are engineered so that their receptors can recognize certain tumor proteins, such as MAGE-A4. Researchers have found that MAGE-A4 is expressed in approximately 82 percent of synovial sarcoma patients (Hum Pathol 2017;61:130-139).
In the research update, we saw that seven out of 12 patients had clinical responses, including five confirmed partial responses that met the response evaluation criteria in solid tumors, known as RECIST 1.1, and two unconfirmed partial responses that remain ongoing at the time of the data cutoff. In one patient, we saw an 86 percent tumor decrease in accordance with RECIST 1.1, with the patient experiencing significant symptom improvement. In the same patient, we also saw a large pleura-based lesion disappear by the Week 6 scan.
Furthermore, 11 out of the 12 patients experienced a clinical benefit from the therapy. This means that all patients' tumors may not have decreased to meet RECIST 1.1 criteria; however, they saw improvement in their quality of life including better breathing, resolution of pain, and increased energy. While these benefits are not within the criteria's requirements, we feel that they are very beneficial to the patient and add a lot of value to a study like this one.
In terms of adverse events, the majority of those experienced by patients with this therapy are in line with those typically experienced by cancer patients undergoing chemotherapy or other cancer immunotherapies. One case of fatal aplastic anemia was reported in one patient with synovial sarcoma in this trial. This event was reported to the FDA.
The patients included in this study are heavily pre-treated and have failed multiple therapies, making the responses and clinical benefit we are seeing quite significant. Based on my research, I believe patients could see an even better response rate when they can receive this treatment earlier after initial diagnosis, including naïve patients. Utilizing this treatment earlier could overall change how we approach synovial sarcoma.
I am excited to see the progress in this field and to see how patients will respond to this type of therapy over a longer amount of time. ADP-A2M4 is now being investigated in a phase II clinical trial, called SPEARHEAD-1, and I am delighted to be one of the investigators in this trial. It is currently enrolling patients with synovial sarcoma and myxoid round cell liposarcoma.
I also hope that the anti-tumor activity—which did not meet the RECIST criteria—reported in patients with other solid tumors, in this ADP-A2M4 phase I trial, will in the future pave the way for responses that will allow more patients in a larger number of solid tumors to benefit from these T-cell therapies.
BRIAN VAN TINE, MD, PHD, is Associate Professor of Medicine and Sarcoma Program Director at Washington University in St. Louis.