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.
Update: This story was originally published on July 28, 2016, and has been updated with new information.
Immunotherapy, which harnesses the power of the immune system to fight disease, has recently shown impressive results in the treatment of multiple cancers. The Food and Drug Administration’s approval of a class of drugs called checkpoint inhibitors has dramatically improved therapeutic options. People with melanoma, lung cancer, kidney cancer, bladder cancer, leukemia, and other cancers may benefit from these drugs.
Researchers at Memorial Sloan Kettering are hoping that this immunotherapy success can be applied to the treatment of sarcomas as well. These rare cancers grow in the body’s connective tissues, including fat, blood vessels, nerves, bones, muscles, and cartilage.
We spoke with MSK medical oncologist Sandra P. D’Angelo about the current state of research, including which clinical trials at MSK are under way or planned to open soon.
Why use immunotherapy as a treatment for sarcoma?
Sarcoma is a devastating disease for which we need more-effective therapies. Sarcoma has more than 50 distinct subtypes, and the threat of metastasis can be high. Depending on the type of sarcoma and its initial size, the disease can spread in some patients who are diagnosed. Men and women whose cancer has spread to other parts of the body often respond to treatment but the duration of benefit can sometimes be short and the side effects can sometimes be tough.
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 of the sarcoma subtypes. Each of these diseases may behave differently and require distinct treatment approaches.
Immunotherapy is an appealing option because it’s designed to empower the immune system to fight many different types of cancer, not just one. My colleague Jedd Wolchok and I worked on immunotherapy treatment for melanoma. He takes the view that it’s often better to treat the person and let their own body treat the tumor.
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 the cells 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 of these approaches to treat cancer.
How is checkpoint inhibitor–based immunotherapy being tested against sarcoma at MSK?
The checkpoint inhibitors we are investigating include the drugs ipilimumab (Yervoy®), nivolumab (Opdivo®), and pembrolizumab (Keytruda®), which we’ve already seen be effective in multiple cancers.
Ipilimumab targets a protein called CTLA-4. In earlier clinical studies, it seemed to have a very minimal effect when used alone against selected sarcomas. The latter drug, nivolumab, targets a different protein, called PD-1. We were struck by the deep and rapid responses in people with melanoma when ipilimumab was combined with nivolumab. We think combination immunotherapy will benefit more people with sarcoma. Much of our efforts are focused on identifying the best drugs to combine for patients.
I led a national phase II clinical trial testing the combination of these drugs in people with metastatic sarcoma. We found that nivolumab and ipilimumab are effective in certain sarcoma subtypes. These include undifferentiated pleomorphic sarcoma and myxofibrosarcoma (both types of liposarcoma) as well as leiomyosarcoma, and angiosarcoma. The tumor responses appeared to be similar to those seen with standard chemotherapy. In addition, the combination of these two drugs was found to be very safe and tolerable. The findings were published in January 2018 in the journal Lancet Oncology. They support future studies of this drug combination for people with specific metastatic subtypes. We are continuing to focus on identifying sarcoma biomarkers that allow us to predict who will respond well to this type of immunotherapy.
We’re also exploring therapies that combine checkpoint inhibitors with new drugs that boost the immune response in other ways. For example, there is an ongoing effort combining nivolumab with NKTR-214. This drug is a modified form of a protein called interleukin-2, which is made by the immune system. NKTR-214 is designed to trigger other cells in the immune system to attack cancer cells. The goal is to see if this combination will increase the likelihood of an immune response for metastatic or locally advanced sarcoma.
In addition, there’s an upcoming study combining pembrolizumab with a drug called epacadostat that will be conducted in collaboration with medical oncologist Ciara Kelly. Tumors often can produce an enzyme called IDO1 to avoid the immune system. Epacadostat blocks this enzyme to help the immune system hit the tumor with its full force.
Most recently, in collaboration with Dr. Kelly, we conducted a clinical trial utilizing TVEC, an attenuated herpes virus injected directly into the sarcoma tumor, in combination with pembrolizumab. This trial just completed patient accrual, and we are currently analyzing the results.
What about the use of adoptive T cell therapy for sarcoma?
We have been collaborating with a company to engineer T cells to fight synovial sarcoma. This type of sarcoma has a specific protein called NY-ESO-1 that is not on other cells. Because of that we are able to target the cancer cells selectively. The treatment is being tested in a pilot study at MSK. The trial involves removing T cells from a person with synovial sarcoma, engineering the cells to recognize the NY-ESO-1 protein, and then giving them back to the person in large numbers.
As of November 2017, 37 patients have received these modified T cells in multiple groups with variations to the treatment approach. Overall, the response rate has been promising. There are ongoing efforts to optimize this treatment approach and determine the best strategy moving forward. We are now in the process of leading a similar effort for people with myxoid liposarcoma. Their tumors also express NY-ESO-1. This trial is actively enrolling patients.
Beyond this specific approach, we are working with MSK investigator Michel Sadelain on a type of adoptive T cell therapy called chimeric antigen receptor (CAR) T cell therapy. CAR T has demonstrated remarkable results in people with chemotherapy-resistant leukemia. We are trying to develop CAR T cells that will target a protein that’s on the surface of many sarcomas. That’s a big project that we’ve been working on for several years. We hope to launch a clinical trial testing this approach in the near future.
What is the biggest 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. The cells all look different under a microscope and have different mutations. 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. 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 people with sarcoma.
Diseases
Comments
Eduardo
Jul 29, 2016 • 10:16 am
Eduardo, thank you for reaching out. Memorial Sloan Kettering does not currently have any clinical trials testing immunotherapy for leiomyosarcoma. However, you can read a recent story about the latest research on this form of sarcoma here:
https://www.mskcc.org/blog/what-s-new-leiomyosarcoma
These are the clinical trials for leiomyosarcoma that are ongoing at MSK:
https://www.mskcc.org/cancer-care/clinical-trials/search?keys=leiomyosa…
There is also one trial listed on the government’s website (clinicaltrials.gov):
https://clinicaltrials.gov/ct2/results?term=leiomyosarcoma+immunotherap…
If you or a loved one would like to make an appointment at MSK for a consultation, please call our Physician Referral Service at
800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Luis
Jul 29, 2016 • 11:04 am
I joined a nivolumab clinical trial in the fall of 2014 and was on it for 1 full year. The end result was that tracked tumors decreased by close to 50%. I was off treatment for 8 months then when the cancer began to grow again (slowly) I was put back on treatment and am responding once again. I owe my life to MSK and their immunotherapy clinical trials. So grateful.
Rene Chee
Jul 31, 2016 • 7:06 pm
I am so encouraged that this double checkpoint inhibitor trial for sarcoma patients is finally starting! 8 years ago, I was diagnosed synovial sarcoma. Even though I had 2 recurrences and metastatic disease, I went through great lengths to harness my immune system against cancer (NY-ESO-1 peptide vaccine, dendritic vaccine, NK cell vaccine, Coley’s Toxins, cryoablation). I am a biology researcher, and the science convinced me that the immune system is capable of curing cancer. I have been cancer-free for the past 3 years. I am so thankful that immunotherapy treatments, such as this trial, are readily available to sarcoma patients now. I hope sarcoma patients will take advantage of this incredible treatment opportunity and emerge cancer-free.
Jay
Aug 16, 2016 • 12:14 am
Metastatic chordoma of the spine… are there any somewhat promising treatments or trials coming down the pipeline outside of what’s already been established as first, second, line treatments for this disease? The CAR T cell therapy sounds exciting. Thanks for what MSKCC and it’s team are working toward.
Hi Jay, we sent your question to one of our sarcoma experts, and he said there are some emerging treatments at MSK. If you’d like to make an appointment, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment.
Danny Chambers
Aug 26, 2016 • 9:01 am
Hello,
Firstly thank you for your research into such a terrible illness, it fills us with confidence that you are exploring alternative therapies which is not typical chemotherapy.
My partner who is just 25 was diagnosed with Renal Dedifferentied Liposarcoma 9 months ago and under went a full nephrectomy. She was not offered any other treatment after this.
Yesterday she was suddenly in severe abdominal pain and was taken into hospital. After a range of CT scans the doctors confirmed two more growths near where the kidney was removed, nearer the colon. They have also confirmed the presence of 7 lumps in the lungs.
We are planning on having the abdominal masses removed straight away but for obvious reasons we want to try all we can to fight the lung growths.
Immunotherapy is something which we have hope in and was wondering if there is any suitable trials or treatments you can offer there to give us a chance of beating this.
We currently live in Singapore but are more than happy to travel there if you have any suggestions or input.
Once again thank you, and really do hope you can help us in this time of need.
Kind Regards,
Danny
Danny, thank you for reaching out. We are sorry to hear about your partner’s situation.
If she would like to speak to someone about coming to Memorial Sloan Kettering for a consultation or possible clinical trial (or sending her records for review), I encourage her to contact our International Center by calling 1 212-639-4900 or going to https://www.mskcc.org/experience/become-patient/international-patients. The email address is international@mskcc.org.
Robyn Shepherd
Sep 16, 2016 • 1:24 am
Memorial Sloan Kettering
Sep 16, 2016 • 8:59 am
In reply to Have you treated anyone with…by Robyn shepherd
Dear Robyn, yes we have treated children with that type of cancer. To browse clinical trials for pediatric sarcomas, please visit https://www.mskcc.org/pediatrics/cancer-care/types/pediatric-sarcomas/c…. If you have questions about any of these studies or would like to make an appointment, please call our Pediatric Department at 212-639-5954. Thank you for reaching out to us.
Alanna Jones
Oct 7, 2016 • 1:37 pm
Memorial Sloan Kettering
Oct 10, 2016 • 1:36 pm
In reply to It is hopeful and promising…by Alanna Jones
Dear Alanna, we are sorry to hear about your father’s diagnosis. If you are interested in making an appointment for him to see one of our specialists, please call our Physician Referral Service at 800-525-2225. Wait times vary and depend on a number of factors, including how long it takes to get his relevant medical records sent to us, but our staff there can answer your questions as to when the first available appointment would be. Thank you for reaching out to us.
Ann
Oct 10, 2016 • 4:28 pm
Thank you to MSK for doing this fantastic research to find a cure for such a horrific and rare form of cancer. My mother is currently battling late stage, aggressive Synovial Sarcoma, and I was wondering if there are any trials she could become involved in, or whom I could contact to register her for future opportunities? Thank you.
Hi Ann, we’re sorry to hear about your mother. If she would like to find out about participating in a trial at MSK, she can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.
Ann
Oct 12, 2016 • 3:07 am
I was diagnosed with leiomyosarcoma in October 2014. The tumor is totally enclosed in the inferior vena cava. I have been on 3 different types of cancer. Gemzar reduced the tumor in half during the first 1-3 ‘drips” but the tumor then stabilized and I took a break (per doctors’ orders). When next checked 2 months later tumor was growing again. Back on Gemzar but tumor continued to grow until original size. New chemo is keeping it at bay right now. My name is on list for clinical trial at MD Anderson.
Any advice, reactions, suggestions?
Dear Ann, we are sorry to hear about your diagnosis. You may be interested in reading a recent blog post we published on what’s new in this area of research: https://www.mskcc.org/blog/what-s-new-leiomyosarcoma. We also offer clinical trials for people with leiomyosarcoma, which are listed here: https://www.mskcc.org/cancer-care/types/uterine-sarcoma/clinical-trials.
If you have any questions about these studies or would like to make an appointment with one of our specialists for a consultation about possible next steps in your care, please call our Physician Referral Service at 800-525-2225. Thanks for reaching out to us.
Julia
Oct 26, 2016 • 11:22 am
My father was diagnosed with leiomyosarcoma (LMS) about 7 years ago and had surgery to remove slow growing tumors. However, about 2 years ago, the disease has metastasized and he is not responding to any conventional treatment or the new chemo that was recently approved. Are there any trials that have proven successful? We are out of state – do you have partnerships with hospitals in Chicago?
Dear Julie, we are sorry to hear about your father’s diagnosis.
Unfortunately, we don’t have any alliances with hospitals in Chicago, but if you are interested in finding a local comprehensive cancer center to see if they offer a trial that’s appropriate for your dad, you may search for one on the National Cancer Institute’s website: https://www.cancer.gov/research/nci-role/cancer-centers/find. Robert H. Lurie Comprehensive Cancer Center at Northwestern University and The University of Chicago Comprehensive Cancer Center are both listed as comprehensive cancer centers.
You might also look for clinical trials in your area on this national database maintained by the National Institutes of Health: www.clinicaltrials.gov.
In case you are interested, MSK does have a couple of open trials evaluating new treatments for people with leiomyosarcoma, which can be found here: https://www.mskcc.org/cancer-care/clinical-trials/search?keys=leiomyosa…. If you have any questions about these studies or would like to make an appointment with one of our specialists to discuss possible next steps in your father’s care, please call our Physician Referral Service at 800-525-2225.
Thank you for reaching out to us.
Uma Maheshwara Rao
Oct 29, 2016 • 9:30 am
Condrosarcoma at Cervical spine c2, C3——-Underwent anterior and posterior surgeries and Radiation in 2013. Now there is a recurrence. Neurosurgeons and oncologists said that it is not possible to remove entire tumor since it is very close to Spinal cord. If it is removed partially, it will grow soon. Finally, I request that is there any solution to my problem.
Memorial Sloan Kettering
Oct 31, 2016 • 10:38 am
In reply to Condrosarcoma at Cervical…by Uma Maheshwara Rao
Debra Gurin
Nov 1, 2016 • 4:50 pm
I recently finished my second occurrence of Pulmonary Artery Angiosarcoma. Chemo saved my life twice but I am nervous for another recurrence and was wondering if there are any trials for a maintenance program? If not, do you think immunotherapy might be an option if I get the disease again? I’d love to know there was something out there for me to try God forbid chemo doesn’t work. When it came back the second time it was in my lungs. I am healthy now but worry for my future.
Thank you!
Debra
Dear Debra, we are sorry to hear about your health issues and are glad to know you are doing well. Fear of recurrence and uncertainty about the future is a common issue for many cancer survivors. You may find it helpful to read one of our previous blog posts that offers some helpful advice in coping with that fear: https://www.mskcc.org/blog/six-tips-managing-fear-recurrence.
If you do experience a recurrence in the future and would like to make an appointment with one of our specialists to discuss possible treatment options, including clinical trials, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.
Deborah Brada
Nov 4, 2016 • 2:47 pm
Memorial Sloan Kettering
Nov 7, 2016 • 10:59 am
In reply to My son has synovial sarcoma…by Deborah Brada
Dear Deborah, we are sorry to hear about your son’s diagnosis. We are actively investigating the use of adoptive T cell therapy for sarcoma. In fact, we are collaborating with a company to engineer T cells to specifically fight synovial sarcoma. 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. To learn more about our work in this area, please read one of our recent blog posts on this topic: https://www.mskcc.org/blog/immunotherapy-offers-new-strategy-treating-s….
If you are interested in making an appointment at MSK to discuss possible treatment options, including relevant clinical trials, for your son, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.
Uma Maheshwara Rao
Nov 19, 2016 • 2:24 am
This is Uma Maheshwara Rao from India. I am suffering from conventional condrosarcoma grade 2 at C spine C2 & C3. I under went 2 surgeries followed by Radiation treatment in 2013. Now there is a recurrence. For which again I underwent surgery, the tumor is not removed completely. Stil I have severe pain from neck to shoulders. Now doctors there is no option for surgery and radiation. Is there immunotherapy for me. Please help me.
Thanks & Regards
Memorial Sloan Kettering
Nov 21, 2016 • 8:58 am
In reply to This is Uma Maheshwara Rao…by Uma Maheshwara Rao
Hi Uma, immunotherapy for sarcoma is still experimental and it’s too early to know which patients it will benefit. You may want to ask your doctor in India about clinical trials, or go to www.clinicaltrials.gov to find out if there are any research studies that you may be able to participate in. Thank you for your comment, and best wishes to you.
Bryan P
Nov 24, 2016 • 12:21 pm
Hi Bryan, we’re sorry to hear your spouse is going through this. If you’d like to talk to an expert at MSK about the clinical trials that may be right for her, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.
Stephanie Manikas
Nov 27, 2016 • 3:41 pm
In August of 2016, my 56 year old mother was diagnosed with an undifferentiated soft tissue sarcoma. October 27th, she had the 17 cm mass removed from her upper left leg. We recently were informed that the cancer metastasized to her lungs. She has no comorbidities and prior to her diagnosis she was very active and healthy. I am wondering what clinical trials may be currently available for her.
Thank you!
Memorial Sloan Kettering
Nov 27, 2016 • 6:48 pm
In reply to In August of 2016, my 56…by Stephanie Manikas
Stephanie, we’re sorry to hear about your mother’s diagnosis. If she would like to learn about clinical trials at MSK, she can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment to discuss her options. If your mother is not in the NYC area and not able to travel, you can go to www.clinicaltrials.gov to look for trials at other hospitals that may be more convenient for your family. Thank you for your comment, and best wishes to you.
Joan Spiegel
Dec 1, 2016 • 4:56 pm
Memorial Sloan Kettering
Dec 5, 2016 • 10:19 am
In reply to My friend was dxd with stage…by joan spiegel
Hi Joan, if your friend would like to arrange for a consultation to find out what trials might be available to her at MSK, she can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.
Stephanie James
Dec 4, 2016 • 10:29 pm
Memorial Sloan Kettering
Dec 5, 2016 • 9:23 am
In reply to Do you have any trials for…by Stephanie James
Hi Stephanie, we do have trials looking at the use of immunotherapy for patients with a number of different kinds of sarcoma. If you would like to learn more, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.
Asma Siddiqui
Jan 28, 2017 • 3:38 pm
Hi my 13 yo daughter with autism has been diagnosed with osteosarcoma stage I , no mets.
I would like her to do immunotherapy first prior to chemotherapy. Do you have studies for this . She has a distal femur fracture as the result of the osteosarcoma. Please get back to me asap.
Many thanks Dr. Siddiqui NJ
Memorial Sloan Kettering
Jan 29, 2017 • 9:53 pm
In reply to Hi my 13 yo daughter with…by Asma siddiqui
Dear Asma, we’re sorry to hear about your daughter’s diagnosis. If you would like to consult with a doctor at MSK about your daughter’s treatment, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.
Daniel
Feb 3, 2017 • 9:14 am
Melissa
Mar 22, 2017 • 11:13 pm
My mother received radiation and then surgical removal/resectioned for a roast size liposarcoma tumor in her retroperitoneal cavity four years ago. it has returned in the same area. She has received 4 Xweek long chemo treatments and awaiting a PET scan. Very healthy otherwise. Is there a immunotherapy program she should be asking about ? thank you for the work you do.
Dear Melissa, we’re very sorry to hear about your mother’s recurrence. It’s possible that she may be able to participate in a clinical trial involving immunotherapy or perhaps instead a targeted therapy. This is something you should discuss with her doctor. If she is interested in coming to MSK for a consultation, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.
Frau Schreiber
Mar 24, 2017 • 9:52 am
Memorial Sloan Kettering
Mar 24, 2017 • 11:28 am
In reply to Any benefits seen in high…by Frau Schreiber
These therapies are still being evaluated in clinical trials, and it is too early to know which types of sarcoma they will be most effective against. If you are interested in participating in one of these trials, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.
Mahesh Patil
Mar 24, 2017 • 11:58 pm
My wife has high grade spindle cell sarcoma tumour(more than 10 cm) in left lung and now metastased to right lung.As per doctors here surgery won’t help as it metastased.Pl indicate if immunotherapy will work for my wife and can I take treatment in India through MSK or what is the option available for treatment
Dear Mahesh, we’re sorry to hear about your wife’s diagnosis. Immunotherapy is still in the early stages of being tested for sarcoma, and it’s too early to know which types it may be effective against. If your wife is interested in coming to MSK as an international patient, you can contact our International Center at international@mskcc.org or go to https://www.mskcc.org/experience/become-patient/international-patients for more information. Thank you for your comment, and best wishes to you and your family.
Alice
Apr 23, 2017 • 3:59 pm
Dear Alice, we’re sorry to hear about your diagnosis. We recommend that you to go www.clinicaltrials.gov to look for trials in Belgium. This database maintained by the US National Institutes of Health includes trials from all over the world. You could also ask your current doctor about referring you to a trial. Thank you for your comment, and best wishes to you.
Laurie
May 24, 2017 • 9:44 am
Dear Laurie, we’re sorry to hear about your daughter’s diagnosis. We do have trials. If you would like to make an appointment for her to have a consultation with one of our expert, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment, and best wishes to you and your family.
Mahir Ali
May 31, 2017 • 7:39 am
hi.my sister is 37 years old. she was operated at MSKCC in 2014 nov for synovial sarcoma of right shoulder after neoadjuvant radiation. she had a local recurrence now in may 2017, a 7cm lesion which surfaced suddenly and grew rapidly to 7cm size. she has undergone excision with wide margins in india this time.She has never taken chemo and doesnt want to go for it. are there any immunotherapy options for preventing recurrence in this case.
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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.
Update: This story was originally published on July 28, 2016, and has been updated with new information.
Immunotherapy, which harnesses the power of the immune system to fight disease, has recently shown impressive results in the treatment of multiple cancers. The Food and Drug Administration’s approval of a class of drugs called checkpoint inhibitors has dramatically improved therapeutic options. People with melanoma, lung cancer, kidney cancer, bladder cancer, leukemia, and other cancers may benefit from these drugs.
Researchers at Memorial Sloan Kettering are hoping that this immunotherapy success can be applied to the treatment of sarcomas as well. These rare cancers grow in the body’s connective tissues, including fat, blood vessels, nerves, bones, muscles, and cartilage.
We spoke with MSK medical oncologist Sandra P. D’Angelo about the current state of research, including which clinical trials at MSK are under way or planned to open soon.
Why use immunotherapy as a treatment for sarcoma?
Sarcoma is a devastating disease for which we need more-effective therapies. Sarcoma has more than 50 distinct subtypes, and the threat of metastasis can be high. Depending on the type of sarcoma and its initial size, the disease can spread in some patients who are diagnosed. Men and women whose cancer has spread to other parts of the body often respond to treatment but the duration of benefit can sometimes be short and the side effects can sometimes be tough.
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 of the sarcoma subtypes. Each of these diseases may behave differently and require distinct treatment approaches.
Immunotherapy is an appealing option because it’s designed to empower the immune system to fight many different types of cancer, not just one. My colleague Jedd Wolchok and I worked on immunotherapy treatment for melanoma. He takes the view that it’s often better to treat the person and let their own body treat the tumor.
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 the cells 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 of these approaches to treat cancer.
How is checkpoint inhibitor–based immunotherapy being tested against sarcoma at MSK?
The checkpoint inhibitors we are investigating include the drugs ipilimumab (Yervoy®), nivolumab (Opdivo®), and pembrolizumab (Keytruda®), which we’ve already seen be effective in multiple cancers.
Ipilimumab targets a protein called CTLA-4. In earlier clinical studies, it seemed to have a very minimal effect when used alone against selected sarcomas. The latter drug, nivolumab, targets a different protein, called PD-1. We were struck by the deep and rapid responses in people with melanoma when ipilimumab was combined with nivolumab. We think combination immunotherapy will benefit more people with sarcoma. Much of our efforts are focused on identifying the best drugs to combine for patients.
I led a national phase II clinical trial testing the combination of these drugs in people with metastatic sarcoma. We found that nivolumab and ipilimumab are effective in certain sarcoma subtypes. These include undifferentiated pleomorphic sarcoma and myxofibrosarcoma (both types of liposarcoma) as well as leiomyosarcoma, and angiosarcoma. The tumor responses appeared to be similar to those seen with standard chemotherapy. In addition, the combination of these two drugs was found to be very safe and tolerable. The findings were published in January 2018 in the journal Lancet Oncology. They support future studies of this drug combination for people with specific metastatic subtypes. We are continuing to focus on identifying sarcoma biomarkers that allow us to predict who will respond well to this type of immunotherapy.
We’re also exploring therapies that combine checkpoint inhibitors with new drugs that boost the immune response in other ways. For example, there is an ongoing effort combining nivolumab with NKTR-214. This drug is a modified form of a protein called interleukin-2, which is made by the immune system. NKTR-214 is designed to trigger other cells in the immune system to attack cancer cells. The goal is to see if this combination will increase the likelihood of an immune response for metastatic or locally advanced sarcoma.
In addition, there’s an upcoming study combining pembrolizumab with a drug called epacadostat that will be conducted in collaboration with medical oncologist Ciara Kelly. Tumors often can produce an enzyme called IDO1 to avoid the immune system. Epacadostat blocks this enzyme to help the immune system hit the tumor with its full force.
Most recently, in collaboration with Dr. Kelly, we conducted a clinical trial utilizing TVEC, an attenuated herpes virus injected directly into the sarcoma tumor, in combination with pembrolizumab. This trial just completed patient accrual, and we are currently analyzing the results.
What about the use of adoptive T cell therapy for sarcoma?
We have been collaborating with a company to engineer T cells to fight synovial sarcoma. This type of sarcoma has a specific protein called NY-ESO-1 that is not on other cells. Because of that we are able to target the cancer cells selectively. The treatment is being tested in a pilot study at MSK. The trial involves removing T cells from a person with synovial sarcoma, engineering the cells to recognize the NY-ESO-1 protein, and then giving them back to the person in large numbers.
As of November 2017, 37 patients have received these modified T cells in multiple groups with variations to the treatment approach. Overall, the response rate has been promising. There are ongoing efforts to optimize this treatment approach and determine the best strategy moving forward. We are now in the process of leading a similar effort for people with myxoid liposarcoma. Their tumors also express NY-ESO-1. This trial is actively enrolling patients.
Beyond this specific approach, we are working with MSK investigator Michel Sadelain on a type of adoptive T cell therapy called chimeric antigen receptor (CAR) T cell therapy. CAR T has demonstrated remarkable results in people with chemotherapy-resistant leukemia. We are trying to develop CAR T cells that will target a protein that’s on the surface of many sarcomas. That’s a big project that we’ve been working on for several years. We hope to launch a clinical trial testing this approach in the near future.
What is the biggest 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. The cells all look different under a microscope and have different mutations. 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. 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 people with sarcoma.
Is there any clinical trial to test immunotheraphy in patients with leiomyosarcoma metastatic?