
Investigators Michel Sadelain (left) and Prasad Adusumilli
In 2013, Science magazine named cancer immunotherapy the scientific breakthrough of the year. It featured two active fields of study at Memorial Sloan Kettering as leading areas of research.
One of those fields is chimeric antigen receptor (CAR) therapy, which is based on the premise that a patient’s own immune cells can be trained to recognize and attack cancer cells. This approach has shown early potential in treating certain kinds of blood cancer, but researchers have yet to determine the best way to apply it to treating solid tumors.
A study published earlier this month in Science Translational Medicine suggests how this technique might be applied to tumors of the pleural cavity, the area in the chest found just outside the lungs. The pleural cavity is the most common location in the body for rare, aggressive tumors called mesotheliomas and is also a frequent site of metastasis for other tumor types, including lung and breast cancers.
“Every year in the United States, about 150,000 new patients are diagnosed with cancer in the pleural cavity, and about 1.5 million procedures are done as a result of these tumors,” says MSK thoracic surgeon Prasad Adusumilli, the first author of the new study. “I’ve focused much of my work the past several years on finding better ways to treat these tumors.”
Finding the Right Target
In CAR therapy for leukemia, immune cells called T cells are genetically engineered to recognize the CD-19 protein, which is found on the surface of blood cells called B cells. Since CD-19 is not present in pleural tumors, investigators needed to identify another target — a protein that’s present in these tumors yet not in most other cell types — in order to protect healthy cells from attack.
They found these attributes in a protein called mesothelin. Mesothelin is present in almost 90 percent of mesotheliomas, as well as 60 percent of lung adenocarcinomas and 35 percent of triple-negative breast cancers (the most difficult-to-treat type of breast cancer). Previous studies conducted by the MSK team showed that the presence of mesothelin indicates that a cancer is more aggressive and less likely to respond to other treatments, such as radiation or chemotherapy.
Back to topPutting the Pieces in Place
For the CAR therapy research to move forward for pleural tumors, the investigators spent several years developing mouse models that closely mimic this type of cancer — the first ever developed.
They also focused on finding ways to manufacture T cells engineered to recognize the mesothelin protein, work led by MSK’s Cell Therapy and Cell Engineering Facility under the direction of Isabelle Rivière.
CAR T cell therapy works by filtering out a patient’s T cells and — outside the body — introducing a new gene into the cells. That gene encodes a receptor that enables the T cells to recognize a protein present on the surface of cancer cells — in this case, the mesothelin protein.
Back to topA Superior Immune Response
In CAR therapy for leukemia, the engineered cells are reintroduced to the patient through the bloodstream, but for pleural tumors the investigators found another way.
“We thought this was going to be a pretty run-of-the-mill animal study, but it turned out to yield a big surprise,” says Michel Sadelain, Director of MSK’s Center for Cell Engineering and the study’s senior author. “We discovered that when we infused the T cells directly into the pleural cavity, the response was 30 times better than infusing them intravenously. The intrapleural infusion was superior in terms of eliminating local tumors, and it yielded a superior overall immune response.”
“We learned that when we administer the T cells directly into the pleural cavity, they all see the cancer immediately,” Dr. Adusumilli adds. “The T cells get activated and divide more quickly. Furthermore, they are able to enter the bloodstream and travel throughout the body, finding and killing cancer cells that are present in other locations.”
In the majority of mice, the tumors were eradicated and didn’t come back. And two further experiments — conducted 100 or 200 days after the mice had been infused with T cells — showed that the immune cells had persisted and still were able to kill the cancer when new tumors were introduced.
Back to topMoving Forward to Trials
Based on the mouse studies, the investigators plan to launch a clinical trial in early 2015 to find out if the treatment is safe for people with solid tumors in the chest cavity.
“Ultimately, patients are the reason we do this research,” Dr. Sadelain concludes. “I’m very proud to work at MSK, where we can develop this kind of approach in the research lab and implement it in the clinic, thanks to our facilities and the depth of our clinical programs.”
Back to topComments
Edwin Goicochea
Dec 4, 2014 • 1:40 PM
Memorial Sloan Kettering
Dec 4, 2014 • 4:01 PM
In reply to Hello, first of all, thanks by Edwin Goicochea
Edwin, thank you for your comment and questions. According to Dr. Adusumilli, “Our institutional immunotherapy research does include identifying tumor mutation targeting immune responses. While the pleural tumors from gastroesophageal cancers are not included in our upcoming clinical trial, we are conducting preclinical work in this area with a goal to translate it into trials in near future.”
Joyce Schmitt
Dec 9, 2014 • 7:25 PM
Good Evening: I am interested in finding out about possible enrolling in this upcoming trial. I have been a patient at msckk for two years. i have triple negative breast cancer which has metastized to my spine and lungs. I recently participated in a trial which was stopped by the sponsor due to the the fact that all patients enrolled were not responding. I am considering participating in a trial run by Dr. Monchok which involves immunotherapy which is an intravenous infusion. Is there anyone I can speak to to find out if and when I can participate in this trial? My oncologist is Dr. Tiffany Traina, who helps me find trials that she thinks are appropriate for me. I thank you for all that your staff does to help and support their patients. Thank you so much and I look forward to hearing from you.
Memorial Sloan Kettering
Dec 9, 2014 • 8:47 PM
In reply to Good Evening: I am interested by Joyce Schmitt
Muneeb Ul Bashir
Jan 14, 2015 • 8:53 AM
Memorial Sloan Kettering
Jan 14, 2015 • 11:11 AM
In reply to Hello, I was operated for by Muneeb ul Bashir
Anonymous
Oct 28, 2015 • 7:28 AM
Memorial Sloan Kettering
Oct 28, 2015 • 9:14 AM
In reply to I am stage 4 rectal patient… by Anonymous
This trial is for patients with mesothelioma, breast cancer, or non-small lung cancer whose tumors express a particular protein, called mesothelin. To find out about trials MSK has open for advanced rectal cancer, you can call our Physician Referral Service at 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.
J Hurst
Dec 6, 2015 • 6:09 PM
Thank you for reaching out. To find out about treatment options for your husband, we recommend you call our Physician Referral Service at 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.
Carolyn Bolton
Feb 28, 2016 • 7:06 PM
Currently in a trial at Duke University Cancer Center. Methylgene 265. NSCLC. Have been through chemo & both upper lobes removed in 2014. Cancer came back in left lower lobe in Oct 2015. After second scan cancer was seen about the size of grains of sand (3). Third scan showed it had grown & according to doctors my only option was a trial drug as mentioned earlier. Surgery, etc. is not advisable. I know you would need all medical records to advise if you could offer other treatments. I am a very active, healthy 68 yr old female. All lab work shows I am right where I need to be with no complications. No health issues other than controlled BP. I am hoping there is something out there for me. The trial drug side effects are brutal & feel due to not being able to eat I will die due to malnutrition therefore I am going to
Withdraw from this trial. With best regards.
Memorial Sloan Kettering
Feb 29, 2016 • 3:57 PM
In reply to Currently in a trial at Duke… by Carolyn Bolton
Carolyn, if you would like to make an appointment at MSK to arrange for treatment or a second opinion, 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.
Thelma Gutfreind
Apr 6, 2016 • 4:58 PM
I now have Stage 4 non small cell adenocarcinoma. A very early metastasis was to a lymph node located just under the pulmonary artery and my heart. It has not responded to radiation or chemotherapy and has sent out cancer cells almost everywhere using pathways of the lymphatic system. I believe my best chance for some quality time--no cure, I understand--would be an immunotherapy or targeted genetic therapy. Do you know where any Medicare approved studies might be found for me???
Memorial Sloan Kettering
Apr 7, 2016 • 9:14 AM
In reply to I now have Stage 4 non small… by Thelma Gutfreind
Dear Thelma, we are sorry to hear that your cancer has spread. Clinical trials are testing immunotherapy drugs in all settings, including as a first-line therapy in patients with advanced lung cancers, and in patients who have previously received chemotherapy.
To browse through and learn more about our clinical trials investigating immunotherapy (and other treatments) for people with advanced non small cell lung cancer, please visit https://www.mskcc.org/cancer-care/types/lung/clinical-trials?keys=&dise…
If you have any questions about these trials or would like to make an appointment for a consultation with one of our specialists, please call our Physician Referral Service at 800-225-2225. Thank you for reaching out to us.
Nick
Nov 17, 2017 • 5:05 AM
My father is at Stage 4 non small cell lung cancer, and it has spread to brain, there are 2 tumors in his brain. Now he is on chemotherapy and WBRT, and the DNA test shows that targeted medicine is not available for him. He doesn't feel any pain from the breast or hard breathing, but feel pain from brain, how do we deal with it later on?
Celia Phillips
Oct 20, 2018 • 11:26 AM
I have triple negative metastatic breast cancer. I had a lumpectomy in Feb. 2013 when the cancer was only at Stage 1 and had 6 weeks of radiation. It has come back in the chest wall completely outside the breast and is now at Stage 4. I had three weeks of radiation recently, and am unsure what should come next as far as drug therapy is concerned. I am 71 years old and wonder if any of your clinical trials apply to my condition. I have already lost weight (and I was thin to start with) and wish to avoid chemo if possible, but will accept if there is nothing else. My oncologist says there is one receptor that is partially receptive, but I worry that may not be enough to uptake the necessary non-chemo drug. Thank you for any insight you may give and thank you for research on triple negative!
Memorial Sloan Kettering
Oct 22, 2018 • 9:34 AM
In reply to I have triple negative… by Celia Phillips
Dear Celia, we’re very sorry to hear about your cancer recurrence. If you are interested in speaking with someone at MSK about whether a clinical trial is right for you, you can call our Patient Access Service at 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.
Hello, first of all, thanks for all your hard work and dedication; you truly are heros. Does your research and/or planned clinical trials involve the sequencing of the tumor's genome in order to identified cells from the immune system that may attack a specific mutation in the malignant cells? Is gastro-esophageal cancer considered a solid tumor in the pleural cavity, and as such be a potential candidate for your upcoming trials? Thank you.