Thursday, July 28, 2016
Soft tissue sarcoma, a diverse group of cancers that arise in the body’s connective tissue, is difficult to treat after it has spread. MSK clinicians are investigating the use of immunotherapy to treat this disease. The main approaches involve checkpoint inhibitors and adoptive T cell therapy, which have shown effectiveness against several other cancers. A few clinical trials have already started at MSK and many more are planned to open soon.
Immunotherapy, which harnesses the power of the immune system to fight disease, has recently shown impressive results in the treatment of melanoma, lung cancer, kidney cancer, bladder cancer, and leukemia. The recent FDA approval of a class of drugs called checkpoint inhibitors has dramatically improved therapeutic options for many patients.
Researchers at Memorial Sloan Kettering are hoping to transfer this immunotherapy success to the treatment of sarcomas, rare cancers that grow in the tissue that connects and supports the organs and other structures in the body.
We spoke with MSK medical oncologist Sandra D’Angelo about the current state of research, including which clinical trials at MSK are under way or planned to open soon.
What’s the rationale for using immunotherapy as a treatment for sarcoma?
Sarcoma is a devastating disease for which we need more effective therapies. It has more than 50 distinct subtypes, and the threat of metastasis is high, affecting up to half of people who are diagnosed. Men and women whose cancer has spread to other parts of the body rarely respond to treatment and have a median survival of just ten to 15 months.
With conventional treatments such as chemotherapy, or even newer targeted therapies, we try to treat the tumor. But it will likely prove difficult to develop a single therapy that would work across all the different sarcoma subtypes because each of these diseases may behave differently and require distinct treatment approaches.
Immunotherapy is an appealing potential option because it’s designed to empower the immune system to fight many different types of cancer, not just one. My colleague Jedd Wolchok, with whom I worked on immunotherapy treatment for melanoma, takes the view that it’s often better to treat the patient and let the patient’s own body treat the tumor.Back to top
What types of immunotherapy are now being investigated for sarcoma?
The main approaches involve checkpoint inhibitors and adoptive T cell therapy. Checkpoint inhibitors are drugs that block specific proteins on the surface of immune T cells. This releases a natural brake on the immune system, allowing it to attack the cancer. Adoptive T cell therapy involves removing T cells from patients and modifying them in a way that enables them to recognize and attack specific molecules on the surface of cancer cells. MSK has led the way in using both these approaches to treat cancer.Back to top
How is checkpoint inhibitor–based immunotherapy being tested against sarcoma at MSK?
The checkpoint inhibitors we are investigating include the drugs nivolumab and ipilimumab, which we’ve already seen be effective in multiple cancers. Earlier clinical studies showed that ipilimumab — which targets a protein called CTLA-4 — seemed to have very minimal effect when used alone against selected sarcomas.
We think combination immunotherapy strategies will benefit more people. We were struck by the deep and rapid responses in melanoma patients when ipilimumab was combined with nivolumab, which targets a different protein called PD-1.
I am leading a national phase II clinical trial testing nivolumab with or without ipilimumab in patients with metastatic sarcoma. This trial has completed enrolling patients and we are now analyzing the data, which we hope to present soon. We will try to determine which patients are responding — and why — and use this information to plan future trials.Back to top
What about the use of adoptive T cell therapy for sarcoma?
We are collaborating with a company to engineer T cells to fight synovial sarcoma, one sarcoma type. Because synovial sarcoma has a specific protein called NY-ESO-1 that is not on other cells, we are able to target the cancer cells selectively. The National Institutes of Health spearheaded this clinical trial, initially in pediatric patients. However, MSK has played a major role in understanding how to extend this therapy to adult synovial sarcoma patients, and we have been able to treat most of the adult patients on this study.
We are now in the process of leading a similar effort for patients with myxoid liposarcoma, whose tumors also express NY-ESO-1. That clinical trial will be opening within the next few months.
Beyond this specific approach, we are working with MSK investigator Michel Sadelain in a type of adoptive T cell therapy called chimeric antigen receptor [CAR] T cell therapy, which has demonstrated remarkable results in patients with chemotherapy-resistant leukemia. We are trying to develop CAR T cells that will target a protein expressed on the surface of many sarcomas. That’s a big project that we’ve been working on for two years, and we hope to launch a clinical trial testing this approach in the near future.Back to top
What is the biggest remaining challenge for using immunotherapy against sarcoma?
The major hurdle is identifying the right strategies for specific subtypes. It’s difficult to know what will work in a particular sarcoma because they all differ in histology — how the cells look under a microscope — and which mutations they carry. There are ongoing efforts to identify sarcoma biomarkers that can help us predict whether a therapy will be effective.
The important point is that there is great potential and hope for immunotherapy to have some effectiveness against sarcoma because both checkpoint inhibitors and CAR T cell therapy have demonstrated success in other cancer types. We hope to continue to figure out ways to extend this benefit to sarcoma patients. We are looking forward to opening up numerous clinical trials here in the next months, keeping MSK at the forefront of sarcoma immunotherapy.Back to top