In June, the U.S. Food & Drug Administration (FDA) issued a ‘safe to proceed’ for the Investigational New Drug (IND) application for NY-ESO-1 TCR/IL-15 NK, an engineered T-Cell Receptor Natural Killer (TCR-NK) cell therapy for advanced synovial sarcoma and myxoid/round cell liposarcoma, being developed by Syena, the oncology-focused product company launched by Replay and MD Anderson.
Replay’s Chief Medical Officer provides further insights into the first clinical trial of NY-ESO-1 TCR/IL-15 NK.
1. Can you explain why you have chosen sarcoma for trials of your investigational TCR-NK cell therapy?
The answer is really two-fold. We focus on the science with everything we do at Replay. Our choice of sarcoma is based on our understanding of science and its potential for patients. NY-ESO-1, the first cancer neoantigen that our therapy is targeting, is an extensively validated tumor-associated antigen expressed on a variety of tumor types, including synovial sarcomas and myxoid/round cell liposarcomas, the subtypes of sarcoma that Replay is focusing on in this trial. Its highly immunogenic nature and its association with these sarcomas give us a strong reason to believe in its promising potential as a target for our novel immunotherapy.
Alongside that, there is the patient need. Synovial sarcoma and myxoid/round cell liposarcoma are amongst the rarest forms of cancers, with a high unmet need, that poses a significant burden on the lives of patients, including a late or incorrect diagnosis and difficulties for patients in accessing appropriate treatment. We need newer, more advanced therapies for these patients which offer greater potential for prolonged survival, reduced risk of side effects and, ultimately, a better quality of life.
2. What is the current treatment pathway for sarcoma patients?
While new treatment options are being introduced and approaches are evolving, the backbone of sarcoma treatment continues to be older, more traditional therapies, such as chemotherapy and radiation therapy, as well as surgery. Historically sarcomas have been difficult to treat, for several reasons. Firstly, there are multiple subtypes of the cancer which have impeded our ability to build a greater knowledge datasets around the disease, then there is its rarity, and finally it is a highly aggressive cancer. Sarcoma is notorious for its ability to spread fast despite initial treatment.
In many cases sarcoma can be present with no specific symptoms, so it’s difficult to catch it and intervene in the initial stages. Overall, this makes treatment of sarcoma extremely challenging. Sarcomas diagnosed in an advanced stage, can unfortunately relapse, with little hope of any viable options. This is why we need to think beyond the current treatment paradigm. We need to develop novel therapies that can break the barriers currently limiting treatment options for sarcoma patients, whilst always ensuring the patient achieves an optimum quality of life. This is what we believe our cell therapy has the potential to achieve.
3. Can you explain a little more about the TCR-NK approach?
This is a novel cell therapy with the potential to transform the current treatment landscape for synovial and myxoid/round cell liposarcoma. We anticipate it will achieve compelling efficacy alongside a reduced treatment burden and a significantly reduced risk to the patient. It is the lead clinical program of Syena, the first-in-class engineered T-Cell Receptor Natural Killer (TCR-NK) cell therapy company that we formed earlier this year with The University of Texas MD Anderson Cancer Center, building on the pioneering science of Professor Katy Rezvani, M.D., Ph.D. The vision behind Syena is really to disrupt the existing cell therapy paradigm with a next generation agent that can bring new options for patients in need. We’ve seen the transformative effect from the likes of engineered CAR T or TCR T-cell therapies that have brought to cancer care, but the field is still plagued by limitations. The inability to treat large patient populations or solid tumors, complex manufacturing remains prohibitively expensive, and with safety challenges. Syena is leveraging the power of NK cells to democratize engineered cell therapy for the treatment of these sarcomas and other cancers. The TCR-NK cell therapy platform combines the advantages of an engineered TCR cancer therapy with the killing power of NK cells. Our therapy offers the possibility of both improved efficacy and safety. These attributes of our therapy are critical for these patients, particularly those who have undergone earlier rounds of treatment resulting in weakened immunity.
4. Will this trial be expanded to other types of cancer?
There will be further updates as we expand to other cancer types. But given what we know about NY-ESO-1 as a target, which is expressed at high levels and in a high frequency in a number of different cancers, we do plan to instigate further trials – the next one will be in relapsed or refractory multiple myeloma. We received approval from the US regulator in July 2023 to begin that trial so plans are well underway.
5. What are the next steps and when can we expect to hear more?
We expect this sarcoma study to begin in the coming months. The team at MD Anderson is close to screening patients. Up to 44 patients will be enrolled, which will generate the critical data set, required to support its continued development. Our priority is identifying the right patients for this study. Firstly, this is a rare cancer. Secondly, this trial is focused on enrolling patients who possess the HLA-A*02 allele HLA haplotype. Haplotypes can be thought of as unique genetic fingerprints that are inherited from the mother and father. HLA haplotypes encode for proteins called human leukocyte antigens (HLA), which, in conjunction with additional antigen processing components within the cell, capture and present fragments of intracellular proteins on the cell's surface. In cancer cells, these HLA molecules display aberrant protein fragments, serving as signals or markers that prompt immune cells to identify and eliminate the malignant cell. In a cancerous cell, the HLA proteins display abnormal fragments which act as a trigger or call-sign for immune cells to destroy that cell.
The HLA-A*02 allele along with NY ESO-1 expression are strong biomarkers for the potential effectiveness of our therapy. Our priority is to develop strategies to find the right patients, considering this is a rare cancer with only a subset of patients who are eligible to take part. You’ll hear details when the trial starts later this year as we expand the program into other cancer types.