Clinical Trials Update

Specific Peptide-Enhanced Affinity Receptor MAGE-A4 T Cells for Synovial Sarcoma

Soft tissue sarcoma is a rare type of cancer that affects the body’s soft tissues, such as muscles, fat and ligaments. There are more than 50 types of soft tissue sarcoma, including synovial sarcoma, which accounts for 5% to 10% of all soft tissue tumors diagnosed each year.

MAGE-A4c1032T for Multi-Tumor is a phase 1, dose-escalation, interventional clinical trial to assess the safety, tolerability and antitumor activity of genetically engineered affinity-enhanced autologous T cells that target the HLA-A2 tissue marker for the treatment of adults with tumors that express the MAGE-A4 protein.

Researchers are currently enrolling patients into the study; eligible participants will have their T cells harvested and sent to the manufacturer for genetic modification. Patients will then receive infusions of autologous MAGE-A4c1032T cells (ADP-A2M4; Adaptimmune).

Brian Van Tine

Cell Therapy Next recently spoke with Brian Van Tine, MD, PhD, an associate professor of medicine in the division of oncology at Washington University School of Medicine and one of the trial’s principal investigators, for an update on the progress of a subset of patients with synovial sarcoma that was presented at this year’s European Society of Medical Oncology Congress in Barcelona.

Q: What was the rationale for conducting this trial?

The MAGE-A4 tumor antigen appears to be an exciting and promising target in synovial sarcoma because it is expressed in about 80% of patients with the disease. Unlike a lot of tumors where MAGE-A4 positivity is between 3% and 10%, most patients with synovial sarcoma express the antigen. Therefore, it was an attractive target in patients with the right HLA.

Q: How is this treatment method novel from previous synovial sarcoma therapies?

The traditional treatments were chemotherapy. As we went into the checkpoint inhibitor era, we found that pembrolizumab (Keytruda; Merck) or ipilimumab (Yervoy; Bristol-Myers Squibb) and nivolumab (Opdivo; Bristol-Myers Squibb) didn’t seem to have activity in synovial sarcoma. [Published studies] showed that synovial sarcoma is a cold tumor and because of that there is a lot of effort through various clinical trials to make them warm. It seemed that this disease was going to need a special, targeted therapy. Indeed, there are two targets: NY-ESO and MAGE-A4. We now have data on using MAGE-A4 that seem very promising.

Q: How would you characterize the effectiveness of previous treatments?

Traditionally, nothing in synovial sarcoma — once it has become metastatic — has been curative. What’s neat about the cellular therapy is outside of a small window of conditioning chemo, once this goes into your body, you treat yourself. We are now at the point in this trial where several patients have been treating themselves for more than 6 months without the need for any other intervention. This gives you the highest quality of life possible — if you are treating yourself and you don’t need other drugs then you feel better.

Q: What do you mean when you say the patients treat themselves?

The T cells used come from the patient. They are taken out of the body with apheresis, modified and infused back. You can look at this as if the patient is treating themselves. If the T cells persist, they will continue to treat themselves if the target is expressed on the tumor.

Q: What is the timeline for the treatment process?

First, we do a screening. We are looking for patients who are HLA-02-positive and, if they are, the patient undergoes a second screening of the MAGE-A4 antigen by immunohistochemistry. If the patient is positive for both then they are assigned to a treatment protocol. The T cells are removed from the body and shipped off for modification by the manufacturer. During this time many patients will need supportive therapies to ensure the disease does not spread. Once manufacturing is complete the patients are given immunosuppressive chemotherapy for 3 days, 4 days before the reinfusion of the modified T cells.

The patient is admitted to the hospital the day of the infusion and kept for at least 3 days. Many patients will experience cytokine release syndrome, which will need to be managed. From this point they are followed by CT scan and treating themselves if they respond to the therapy.

Source: American Cancer Society

Q: Are there any treatment-related side effects other than CRS?

There are other hematologic side effects that accompany the preconditioning therapy. Some patients may also experience problems with infection from the preconditioning regimen. This is the first synovial sarcoma trial that has shown that CRS corresponds with response: those who have a response seem to have CRS while those who don’t respond to therapy do not get CRS.

Q: When did you start enrolling patients and how many of you treated so far?

We started treating patients approximately 6 months ago, and I have treated four of the 12 patients who have enrolled in the trial.

Q: Your preliminary data presented at ESMO showed effective disease control but no complete responses, is that correct?

Yes. So, in that sense this is kind of an interesting quandary right now. We still are investigating, and we know that there were five confirmed partial responses at this point, with the best responses being down by 80%. Eleven have shown stable disease and only one patient progressed.

Q: What do you envision for this treatment? Is it something that might be used in combination with other therapies in the future?

I would love to see something like this, if we can prove efficacy, moving to a much earlier line, let’s say, a frontline therapy and maybe change how we approach this disease. The responses so far are dramatic, and these are all in heavily pretreated patients. So, if we provided this therapy earlier on you may see a better response rate in these patients. This is the most promising thing I’ve seen in synovial sarcoma in a very long time.

Q: Is there anything else you think that clinicians should know about this research and the use of this cell therapy?

From this sarcoma doctor’s perspective, it’s important to know this therapy is available, but I feel that all patients with sarcoma should be screened for their HLA and MAGE-A4 because of the number of T-cell therapy opportunities for this very rare subset of sarcoma. There are options that don’t exist for a lot of people that may exist for this patient population, and no one should miss an opportunity to see if we can use their own cells to eliminate tumors. – by Drew Amorosi

Disclosures: Van Tine reports travel support from Adaptimmune. This study is sponsored by Adaptimmune.

Soft tissue sarcoma is a rare type of cancer that affects the body’s soft tissues, such as muscles, fat and ligaments. There are more than 50 types of soft tissue sarcoma, including synovial sarcoma, which accounts for 5% to 10% of all soft tissue tumors diagnosed each year.

MAGE-A4c1032T for Multi-Tumor is a phase 1, dose-escalation, interventional clinical trial to assess the safety, tolerability and antitumor activity of genetically engineered affinity-enhanced autologous T cells that target the HLA-A2 tissue marker for the treatment of adults with tumors that express the MAGE-A4 protein.

Researchers are currently enrolling patients into the study; eligible participants will have their T cells harvested and sent to the manufacturer for genetic modification. Patients will then receive infusions of autologous MAGE-A4c1032T cells (ADP-A2M4; Adaptimmune).

Brian Van Tine

Cell Therapy Next recently spoke with Brian Van Tine, MD, PhD, an associate professor of medicine in the division of oncology at Washington University School of Medicine and one of the trial’s principal investigators, for an update on the progress of a subset of patients with synovial sarcoma that was presented at this year’s European Society of Medical Oncology Congress in Barcelona.

Q: What was the rationale for conducting this trial?

The MAGE-A4 tumor antigen appears to be an exciting and promising target in synovial sarcoma because it is expressed in about 80% of patients with the disease. Unlike a lot of tumors where MAGE-A4 positivity is between 3% and 10%, most patients with synovial sarcoma express the antigen. Therefore, it was an attractive target in patients with the right HLA.

Q: How is this treatment method novel from previous synovial sarcoma therapies?

The traditional treatments were chemotherapy. As we went into the checkpoint inhibitor era, we found that pembrolizumab (Keytruda; Merck) or ipilimumab (Yervoy; Bristol-Myers Squibb) and nivolumab (Opdivo; Bristol-Myers Squibb) didn’t seem to have activity in synovial sarcoma. [Published studies] showed that synovial sarcoma is a cold tumor and because of that there is a lot of effort through various clinical trials to make them warm. It seemed that this disease was going to need a special, targeted therapy. Indeed, there are two targets: NY-ESO and MAGE-A4. We now have data on using MAGE-A4 that seem very promising.

Q: How would you characterize the effectiveness of previous treatments?

Traditionally, nothing in synovial sarcoma — once it has become metastatic — has been curative. What’s neat about the cellular therapy is outside of a small window of conditioning chemo, once this goes into your body, you treat yourself. We are now at the point in this trial where several patients have been treating themselves for more than 6 months without the need for any other intervention. This gives you the highest quality of life possible — if you are treating yourself and you don’t need other drugs then you feel better.

PAGE BREAK

Q: What do you mean when you say the patients treat themselves?

The T cells used come from the patient. They are taken out of the body with apheresis, modified and infused back. You can look at this as if the patient is treating themselves. If the T cells persist, they will continue to treat themselves if the target is expressed on the tumor.

Q: What is the timeline for the treatment process?

First, we do a screening. We are looking for patients who are HLA-02-positive and, if they are, the patient undergoes a second screening of the MAGE-A4 antigen by immunohistochemistry. If the patient is positive for both then they are assigned to a treatment protocol. The T cells are removed from the body and shipped off for modification by the manufacturer. During this time many patients will need supportive therapies to ensure the disease does not spread. Once manufacturing is complete the patients are given immunosuppressive chemotherapy for 3 days, 4 days before the reinfusion of the modified T cells.

The patient is admitted to the hospital the day of the infusion and kept for at least 3 days. Many patients will experience cytokine release syndrome, which will need to be managed. From this point they are followed by CT scan and treating themselves if they respond to the therapy.

Source: American Cancer Society

Q: Are there any treatment-related side effects other than CRS?

There are other hematologic side effects that accompany the preconditioning therapy. Some patients may also experience problems with infection from the preconditioning regimen. This is the first synovial sarcoma trial that has shown that CRS corresponds with response: those who have a response seem to have CRS while those who don’t respond to therapy do not get CRS.

Q: When did you start enrolling patients and how many of you treated so far?

We started treating patients approximately 6 months ago, and I have treated four of the 12 patients who have enrolled in the trial.

Q: Your preliminary data presented at ESMO showed effective disease control but no complete responses, is that correct?

Yes. So, in that sense this is kind of an interesting quandary right now. We still are investigating, and we know that there were five confirmed partial responses at this point, with the best responses being down by 80%. Eleven have shown stable disease and only one patient progressed.

PAGE BREAK

Q: What do you envision for this treatment? Is it something that might be used in combination with other therapies in the future?

I would love to see something like this, if we can prove efficacy, moving to a much earlier line, let’s say, a frontline therapy and maybe change how we approach this disease. The responses so far are dramatic, and these are all in heavily pretreated patients. So, if we provided this therapy earlier on you may see a better response rate in these patients. This is the most promising thing I’ve seen in synovial sarcoma in a very long time.

Q: Is there anything else you think that clinicians should know about this research and the use of this cell therapy?

From this sarcoma doctor’s perspective, it’s important to know this therapy is available, but I feel that all patients with sarcoma should be screened for their HLA and MAGE-A4 because of the number of T-cell therapy opportunities for this very rare subset of sarcoma. There are options that don’t exist for a lot of people that may exist for this patient population, and no one should miss an opportunity to see if we can use their own cells to eliminate tumors. – by Drew Amorosi

Disclosures: Van Tine reports travel support from Adaptimmune. This study is sponsored by Adaptimmune.