In the Lab

On Cancer: New Technique Could Make Cell-Based Immune Therapies for Cancer Safer and More Effective

By Julie Grisham, MS, Science Writer/Editor  |  Tuesday, December 18, 2012
Pictured: Michel Sadelain Michel Sadelain, Director of the Center for Cell Engineering

A team from Memorial Sloan Kettering has reported a new technique that could allow the development of more-specific, cell-based immune therapies for cancer. These types of treatments — which make use of patients’ own immune cells that have been enhanced in the laboratory — have shown some early success in the treatment of blood cancers including certain types of leukemia.

For most cancers, however, cell-based therapies have been harder to develop, in large part because it has been difficult for investigators to train immune cells to attack cancer cells without damaging normal, healthy cells in the body.

“We are getting better at working with patients’ immune cells and enhancing them so that we can get a powerful immunological response against cancer,” says Michel Sadelain, Director of Memorial Sloan Kettering’s Center for Cell Engineering, who led the study. “The dilemma now is that we are concerned with limiting these responses and making them as targeted as possible to avoid potentially harmful side effects. This new study helps us move toward that goal.”

“As Targeted as Possible”

The treatment approach, known as adoptive cell transfer (ACT), involves engineering an immune cell called a T cell. Also called T lymphocytes, T cells are a type of white blood cell. They work by recognizing specific antigens — proteins on the surfaces of invading cells — and mounting an immune response against these invaders.

In the ACT process, T cells are removed from a patient and a gene is added to allow the T cells to recognize a certain antigen on the surface of a cancer cell. The enhanced T cells are grown in the laboratory and then infused back into the patient to seek out and attack cancer cells.

Cancer cells overproduce certain antigens, which can help T cells to recognize them, but those same antigens are often found in lower levels on healthy cells. “There are very few antigens, if any, that are found only on cancer cells,” Dr. Sadelain explains. This means that T cells engineered to recognize a certain antigen could attack normal cells that have that same antigen as well.

“Now we are bringing in a completely new concept,” he adds. “If there is no single unique antigen that is found on the surface of the cancer cell we want to target, we instead create T cells that recognize two different antigens found on the tumor cell — a signature that will be unique to that type of cancer — and only attack cells with both antigens, sparing the normal cells that express either antigen alone.”

Balanced Signaling

The new technique makes use of two kinds of receptors: chimeric antigen receptors (CARs), which allow T cells to target antigens on the surface of a tumor cell, and chimeric costimulatory receptors (CCRs), which allow T cells to recognize a second antigen.

The CAR and the CCR work together through a process known as balanced signaling, in which the presence of either antigen on its own is not enough to trigger the immune response. Only tumor cells that carry both antigens will be targeted.

In the study, which was published online December 16 in Nature Biotechnology, the team created T cells that carried receptors for two antigens found in prostate cancer cells: a CAR for an antigen called PSMA and a CCR for an antigen called PSCA. The investigators then generated mouse models of prostate cancer and infused the mice with the engineered cells. They found that the T cells attacked only tumors that carried both antigens. The study's first author was Christopher Kloss, a graduate student in the Weill Cornell Graduate School of Biomedical Sciences who is a member of Dr. Sadelain's laboratory.

“We are the first to test this concept and show that it works,” Dr. Sadelain concludes. “We plan to develop clinical trials based on this approach, although we have not yet decided whether the first study will be a trial for prostate cancer or for a different type of cancer using two other antigens. Ultimately, our goal is to create targeted immunotherapies that are both potent and safe for patients.”

This work was supported by philanthropic funds provided by Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, The Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center, The Major Family Fund for Cancer Research at Memorial Sloan Kettering, Mr. and Mrs. Joel S. Mallah, and Mr. Lewis Sanders.

Comments

Since May 2011 I have been a volunteer in a Clinical Trial at NIH/NCI in Bethesda, MD, Protocol 09-C-0139, A pilot study of vaccination with Epitope-Enhanced TARP Peptide and TARP Peptide-Pulsed Dendritic Cells in the Treatment of Stage DO Prostate Cancer. I participated in the trial every 3 weeks
from May to Nov 2011; 4 times (every 12 weeks) in 2012. and am scheduled for 5 more appointments (again every 12 weeks) in 2013. I feel absolutely great and hopefully the research is being shared within the cancer research community.
I would be more than happy to provide any details.

Anyone studies of Immucin in the US?

I was treated in 1992 with immunotherapy, in a phase II study with IL2.
My diagnosis was metastatic melanoma stage 4, primary on my chest
wall in 1983, mets in pancreas & liver 1992. 2 major surgeries, 6 courses
of IL2 in-patient at St. Thomas, Nashville & Williamson Cnty, Franklin, TN respectively. My Oncologist is Dr. Robert K. Oldham and my 2nd surgeon
(major liver resection) is Dr. Richard Gere, from M. Sloan-Kettering. Now it
is 01/09/2012.

My sister was diagnosed with liver cancer 2 months ago and is undergoing chemotheraphy treatments. However, she having a lot of difficulty with the side-effects and what's worse is that they won't tell her how long the treatments will continue. In the meantime, she gets nausea & vomiting from the morphine pills she has to take for the pain and consitpation which doesn't allow her to eat well. She also has swelling in her leg. She's not any worse, but she also not feeling any better, so we're at our wits end here.

We encourage you to discuss these concerns with your sister's healthcare provider. Thank you for your comment.

Does the research have any relation to the immunologic research being funded by the NCI and managed thru the Fred Hutchinson Clinic based, to a degree, on the original but ancient work of Dr Coley in 1890's at MSK?

According to Dr. Sadelain, there are many centers in the United States studying immunology as it relates to cancer. Several of them are investigating
engineered T cells as a potential treatment for cancer. Memorial Sloan-Kettering is a leader in the design of chimeric antigen receptors and other related strategies, as exemplified in this latest paper. Thanks for your comment.

I would like to know if this new research would be useful to patients with multiple myloma, which is also a cancer of the blood.

We spoke with Dr. Sadelain, and he says, "The principle described in this paper is indeed applicable to many tumor types, including myeloma. Myeloma happens to be one of our priorities, although we are not yet funded to proceed with it." Thanks for your comment!

I have been told by my local endocrinologist that the nodules on my thyroid gland can be ignored regardless of the fact that they have increased from 2 to 8 in the last year, since biopsies are all negative for cancer. Two are large and a bit uncomfortable.. so am I wrong to be concerned,? I have Hashimotos, disease and on synthroid for the last 2O years.. Do I need a second opinion?

Thank you for your comment. Unfortunately, we are unable to answer personal medical questions on our blog. If you'd like to make an appointment for a second opinion at Memorial Sloan-Kettering, please call 800-525-2225.

My sister was diagnosed with Uterine Leiomyosarcoma and had several surgeries, then chemo with two combined drugs (recommended by Sloan-Kettering). Upon recurrence and after more surgery, she is now on Trabectedine (Yondelis from PharmaMar) and the tumor is stabilzed, but side effects are very hard on her. Any hope from Immunotherapy? Any other suggestions are appreciated! Thanks!

Thank you for your comment. Unfortunately, we are unable to answer personal medical questions on the blog. We encourage you to speak with your sister's physicians at Memorial Sloan-Kettering about this question.

Are there any results or experience of any kind with cell-based immunotherapy treatment of Uterine Leiomyosarcoma? Thanks again...

We spoke to Dr. Sadelain, and he said this approach potentially could be applied to sarcomas, but Memorial Sloan-Kettering does not have an active program in that area at this time. The National Cancer Institute does have a trial open for certain sarcomas. Thanks for your comment.

Would this approach work for mesothelioma?

Thank you for your comment. This research is still in the early stages, and it is too soon to know which cancers it may be successful in treating.

Since this original article, have any trials been initiated or are any in the works to try designer T cells in advanced prostate cancer? Thank you.

Thank you for your comment, Andrea. We have recently opened a clinical trial for patients with prostate cancer: http://www.mskcc.org/cancer-care/trial/09-036.

Are there any plans to try this treatment with metastatic ocular melanoma? My daughter has Stage 4 and we are obviously looking at trials. My (uninformed but energetic) research indicates that ocular melanoma has some unique genetic properties.

Basil, we consulted with MSKCC physician Judd Wolchok, who informed us that the National Cancer Institute has an adoptive cell transfer protocol for ocular melanoma.

To learn more about this trial, you can call the National Cancer Institute’s Cancer Information Service at 800-4CANCER (800-422-6237).

Thank you for your comment.

I have had two Liposarcoma tumours removed since November 2008, when a large tumour was removed from my left lower abdomen and upper thigh, followed by 30 daily radio therapy sessions, the second was a recurrence a little further back but it was mixed up with my Femoral artery and nerve, both of which were removed with the tumour. The artery was replaced with some vein taken from my right thigh but the nerve is gone and I am now not able to move my lower leg forward from the knee.

I now have a third recurrence which is still further back close to the inside of my left rear pelvis, I am advised that surgery is not an option as it would cause more problems than leaving it were it is.

I have had five cycles of 150 mg of Doxorubicin, which has helped stabilised the tumour and relieved some of the nerve pressure but not removed it. I am now looking forward to more Chemotherapy but as yet do not know what it will be.

I wish to offer myself as a volunteer should you require any, I am nearly 73 so have had the best of my life and hopefully what's left could be useful to future cancer sufferers.

Bill, thank you for your comment. You may be interested in joining Connections, our online community for Memorial Sloan-Kettering patients, caregivers, survivors, and friends to exchange support, information, and inspiration. This link has instructions for how to join the community:
http://www.mskcc.org/cancer-care/counseling-support/connections-online-community

I have read that it is hoped to carry out T-cell trials for lung cancer next year. Is this just for small-cell cancers or for others? My wife has a non small-cell cancer (EFGR mutation) and has been taking gene therapy for about 2 years (Gefitinib). We understand that the tumour is likely to mutate further, making Gefitinib ineffective. Are the proposed trials likely to be relevant here?

Jon, we are looking into this and hope to have an answer for you soon. Thank you for your comment.

Hi, Jon. We sent your question to Dr. Sadelain, who responded, "We are planning a trial utilizing CAR-targeted T cells in non-small cell lung cancer in patients whose tumors express mesothelin. The trial will open in 2014 if all preparations go well and advance swiftly." Thank you for your comment.

Will there be any trials for mestasais of the lungs due to Osteosarcoma? My 17-year-old son has done first tier 4 drug chemo, then gemcidabine and abraxane. But nothing has helped. We did DNA testing with Foundation One and he has a TP 53 mutation along with a TSC mutation. So he now is on rarapune and Sorafaneb. He is a strong kid and a fighter. Thank you!

Dear Terry, unfortunately we are unable to answer specific medical questions on our blog. We did forward your inquiry to one of our pediatric oncologists who provided a general response: "There may be one or more clinical trials for patients with osteosarcoma that has metastasized to the lungs, but that won't be for at least 1 to 2 years. If laboratory studies show that a protein called GD2 can be targeted on osteosarcoma as well, we may have a trial open sooner, but that is unlikely to help someone who is searching for newer treatment now." If you would like to make an appointment with one of our specialists for your son, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out. -Esther

I hace insular thyroid cancer date surgery 2006 . I have had 3 dose iodine radition at UCSF ,It 7years later and tumor maker 317 3nodule in left lung could be cancer, tried biopsy lung,no tissue gotten ,nodule in lung 9mm. where is there treatment for my immunity system to fight the cancer I have? Still a little cancer in my neck. I think the lowest my tumor maker been is 6.7 after 3 radation treatment got all togather 400 mg

Donna, unfortunately we are unable to answer specific medical questions on our blog. 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 http://www.mskcc.org/cancer-care/appointment. Thanks for your comment.

ok thanks ,I will call your referral Service on Monday
Donna

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