Human CAR T cells have been engineered to produce a protein that could treat lymphoma.
Memorial Sloan Kettering researchers have developed a potentially powerful lymphoma treatment using modified immune cells that function as on-site “micro-pharmacies,” churning out proteins for therapeutic effect. In experiments with human tumors transplanted into mice, the new immunotherapy approach produced significant responses, raising hopes that this technique could someday offer an effective way of treating this disease and possibly other cancers.
The technique represents a new twist on a form of immunotherapy called chimeric antigen receptor (CAR) T cell therapy, which has demonstrated remarkable results in patients with other blood-related cancers. CAR T cell therapy involves removing immune T cells from a patient, genetically altering them to fight cancer, and giving them back to the patient in vast numbers.
Historically, this form of therapy has aimed to give immune cells the information they need to better recognize tumor cells as foreign and attack them. The new technique illustrates an untapped potential of CAR T cells to act as targeted delivery vehicles by revamping them to produce anticancer agents.
“This form of treatment could be very effective because the CAR T cells continuously produce the protein right where it is needed,” says MSK cancer biologist Hans-Guido Wendel, who led an international team developing the novel technology that included Karin Tarte of the University of Rennes, France. “It could increase the on-target therapeutic activity and also reduce side effects of cancer treatments because it’s restricted to the tumor sites.”
Disrupted Crosstalk Leads to Lymphoma
The researchers devised the innovative approach after making an important discovery about the biology of lymphomas, which usually arise in white blood cells called B cells and are characterized by uncontrolled growth. The researchers identified a critical pathway that is disrupted in approximately 75 percent of follicular lymphomas, a subset of B cell lymphoma.
The pathway involves an interaction between two receptors on the surface of B cells, proteins called HVEM and BTLA. Normally, these receptors communicate with each other to keep B cells’ growth at a normal rate. If this communication is disrupted — if either receptor is not functioning properly — the cells will proliferate out of control.
Dr. Wendel and colleagues found that the gene for HVEM is mutated in most follicular lymphomas, producing a faulty HVEM protein that perturbs the interaction with the BTLA receptor that sits on the surface of the cancerous B cells. This accessible location suggested that it might be possible to deliver the HVEM protein therapeutically and restore its cancer-suppressing function.
“The challenge became finding a way to get HVEM to the cancer cells,” Dr. Wendel says. “It’s a big protein that’s very difficult and expensive to manufacture, and if you tried injecting it, you would need a much higher concentration because it binds in a lot of places you don’t want it to. So we decided to see if we could engineer T cells to make the protein instead and also deliver it to the tumor cells.”
Back to topCAR T Cells Drawn to the Cancer Site
The research team used human CAR T cells engineered to seek out cells expressing the CD19 protein, which is made by all B cells, both cancerous and normal. CD19 CAR T cells naturally home in on B cells and have recently produced stunning results in treating chemotherapy-resistant leukemia.
The research team modified the CD19 CAR T cells so that they would continuously produce the HVEM protein. “The CAR T cells pump out the protein for several weeks in one specific area — which is near the cancer cells,” Dr. Wendel says.
When injected into mice that contained implanted grafts of human follicular cell lymphoma, the cells produced therapeutic responses that were far more significant than when using control CD19 CAR T cells that did not produce HVEM.
The researchers reported their results online today in the journal Cell.
“This shows a feasible way to put the brakes back on lymphoma cells by restoring the HVEM-BTLA interaction,” Dr. Wendel says.
He adds that additional studies are needed to validate the effectiveness of this approach. Darin Salloum, a postdoctoral research fellow in Dr. Wendel’s lab, is further modifying the CAR T cells to produce altered versions of the HVEM protein in the hopes of making the treatment even more effective. Ultimately, pharmaceutical or biotechnology companies can license the technology to conduct a clinical trial.
“Potentially, engineered T cells that function as ‘micro-pharmacies’ and deliver a range of anticancer drugs could transform the way we treat lymphomas and possibly other blood cancers as well,” Dr. Wendel says.
Comments
Keith Happ
Sep 29, 2016 • 6:09 PM
Memorial Sloan Kettering
Sep 30, 2016 • 9:44 AM
In reply to are you doing anything for… by keith happ
Dear Keith, we are investigating the effectiveness of new treatments, including immunotherapy, for people with advanced ovarian cancer. To browse through these clinical trials, please visit: https://www.mskcc.org/cancer-care/types/ovarian/clinical-trials. If you have questions about any of these studies or would like to make an appointment for a loved one, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.
Yadira
Sep 29, 2016 • 8:11 PM
Hi Yadira, we recommend that you contact our Financial Assistance Program. You can go to https://www.mskcc.org/insurance-assistance/assistance to learn more. Thank you for your comment.
Mike Reardon
Oct 24, 2016 • 1:15 PM
Memorial Sloan Kettering
Oct 25, 2016 • 4:53 PM
In reply to Will this new therapy work… by Mike reardon
Mike, thank you for your question.
This technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
Here is a list of clinical trials at MSK for CLL:
https://www.mskcc.org/cancer-care/types/leukemias/clinical-trials?keys=…
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at
800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Ann Stevens
Oct 24, 2016 • 1:21 PM
Ann, thank you for your question.
This technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may want to check this link for a listing of clinical trials at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at
800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Luigi OB
Oct 24, 2016 • 1:25 PM
Luigi, thank you for reaching out.
This technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may want to check this link for a listing of clinical trials at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at
800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Vonalda Utterback
Oct 24, 2016 • 1:39 PM
Memorial Sloan Kettering
Oct 25, 2016 • 4:58 PM
In reply to Thank you for this… by Vonalda Utterback
Volanda, thank you for your question.
This technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may want to check this listing of clinical trials at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at
800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Nancy Holder
Oct 24, 2016 • 2:03 PM
Memorial Sloan Kettering
Oct 25, 2016 • 5:03 PM
In reply to My son, David Holder, was… by Nancy Holder
Nancy, we offer our deep condolences for the loss of your son. This technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, we cannot yet know if it will translate into a treatment for non-Hodgkins Lymphoma.
Deborah P
Oct 24, 2016 • 2:11 PM
Memorial Sloan Kettering
Oct 25, 2016 • 5:07 PM
In reply to Do you see HVEM therapy for… by Deborah P
Deborah, thank you for reaching out. Thank you for your question.
This immunotherapy technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically. It is very possible that genomic testing and targeted drug treatment could someday be used in combination with this or a different immunotherapy.
You may be interested in checking this listing of clinical trials at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at
800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Barbara Ornelas
Oct 24, 2016 • 3:02 PM
Memorial Sloan Kettering
Oct 25, 2016 • 5:08 PM
In reply to Would this therapy possibly… by Barbara Ornelas
Barbara, thank you for reaching out.
This technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may want to check this listing of clinical trials at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at
800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
E Van Cleef
Oct 24, 2016 • 3:05 PM
Memorial Sloan Kettering
Oct 26, 2016 • 10:11 AM
In reply to Would this be a potential… by E Van Cleef
Good morning, this technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may want to check this link for a listing of clinical trials at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Thank you for reaching out to us.
John
Oct 24, 2016 • 4:13 PM
Dear John, this technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may be interest in browsing through this listing of clinical trials at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Thank you for reaching out to us.
Jackie
Oct 24, 2016 • 5:30 PM
Memorial Sloan Kettering
Oct 26, 2016 • 10:16 AM
In reply to Will this be a treatment for… by Jackie
Dear Jackie, this technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may be interested in viewing this listing of clinical trials at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Thank you for your question.
Mario Careaga
Oct 24, 2016 • 5:41 PM
Memorial Sloan Kettering
Oct 26, 2016 • 10:18 AM
In reply to Wen will the trials be… by Mario Careaga
Dear Mario, thank you for your kind words!
This technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available in clinical trials.
You may want to check this link for a listing of clinical trials that are currently open at MSK for people with lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Thank you for reaching out.
Regina Warren
Oct 24, 2016 • 9:24 PM
Memorial Sloan Kettering
Oct 26, 2016 • 10:20 AM
In reply to Anyone working on whether… by Regina warren
Dear Regina, this technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may want to check this link for a listing of clinical trials that are currently open at MSK for lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Thank you for reaching out to us.
Jan Deierling
Oct 24, 2016 • 10:57 PM
Donna M Lombari
Oct 25, 2016 • 4:36 PM
I found this research to be amazing!
I am not sure it would pertain to me. I have been
diagnosed with marginal zone B cell lymphoma
located in front of my skull which the doctors
at Dana Farber said is unusual along with this form
of lymphoma being only 3% of the population.
Could this be a form of treatment for me?
Memorial Sloan Kettering
Oct 26, 2016 • 10:22 AM
In reply to I found this research to be… by Donna M Lombari
Dear Donna, we are sorry to hear about your diagnosis.
This technology is still in an early, investigative stage, so while we are very hopeful it will lead to effective treatments for various lymphomas and possibly other cancers, it is not possible at this point to predict if it will translate into therapies or when it might be available clinically.
You may be interested in checking out this listing of clinical trials open at MSK for people with lymphoma:
https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials
If you would like to make an appointment with a Memorial Sloan Kettering physician to discuss possible next steps in your care, please call our Physician Referral Service at 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Thank you for reaching out to us.
Bridget Hobson
Oct 27, 2016 • 5:08 PM
Memorial Sloan Kettering
Oct 28, 2016 • 10:02 AM
In reply to I know you are in early… by Bridget Hobson
Bridget, thank you for your question. Unfortunately, it is not possible at this time to know whether this approach will have effectiveness agains follicular lymphoma.
You might want to check this government listing of all open clinical trials for follicular lymphoma:
https://clinicaltrials.gov/ct2/results?term=%22follicular+lymphoma%22&r…
If you would like to make an appointment with a Memorial Sloan Kettering physician to discuss possible next steps in your care, please call our Physician Referral Service at 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment
Thank you for reaching out to us.
Eric Stewart
Oct 27, 2016 • 5:26 PM
Memorial Sloan Kettering
Oct 31, 2016 • 11:56 AM
In reply to Hopefully getting funded for… by Eric Stewart
Eric, thank you for your question. I believe you are referring to work that is going on at Northwestern University:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418545/
At MSK, there is work on different types of nanoparticles (which may be related):
HDL nanoparticles for imaging tumor-associated macrophages: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737475/
Nanoparticles for targeted delivery of drugs to cancer, including lymphoma: https://www.mskcc.org/blog/hacking-metastasis-nanotechnology-researcher…
Nanoparticles to find cancer in lymph nodes: https://ncats.nih.gov/pubs/features/improved-cancer-treatments
Todd Berardelli
May 27, 2017 • 11:09 AM
Memorial Sloan Kettering
May 30, 2017 • 1:04 PM
In reply to Are you doing anything with… by Todd Berardelli
Dear Todd, we do not currently have any trials looking at CAR T cell therapies for colorectal cancer, but we have a number of trials for colorectal cancer, including several that involve other types of immunotherapy. If you are interested in learning more and possibly making an appointment, 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.
are you doing anything for sage 4 ovarian cancer?