Longest-Running CAR T Trial Shows Which Patients Benefit Most, Have Fewest Side Effects

By Matthew Tontonoz,

Wednesday, January 31, 2018

Medical oncologist Jae Park
Summary

For adults with relapsed leukemia, CAR T cell therapy is a potentially lifesaving treatment option. A clinical trial conducted at Memorial Sloan Kettering shows the long-term benefit of the approach and suggests ways to make it safer and more effective.

Results published today from the longest-running clinical trial of chimeric antigen receptor (CAR) T cell therapy for cancer offer key insights into factors affecting the safety and effectiveness of this groundbreaking immunotherapy treatment.

Memorial Sloan Kettering scientists report in the New England Journal of Medicine that adults with acute lymphoblastic leukemia (ALL) who received CAR therapy responded better if they had a small amount of disease at the time of treatment. Compared with patients who had a greater amount of disease, those in the low-disease category lived significantly longer and experienced fewer life-threatening side effects.

The eagerly awaited findings are based on an analysis of data from 53 adults with ALL who were treated with CAR therapy at MSK. The maximum follow-up time was five and a half years, with a median of 29 months. The overall median survival was 12.9 months. For those in the low-disease category (defined as less than 5% leukemia cells in the bone marrow), the median survival was 20.1 months.

Strikingly, about 50% of people in the low-disease category were still alive and well after five years. Doctors speculate that they may be cured.

This is the longest follow-up study of people with ALL treated with CAR therapy. It confirms the power of CAR T cells as an effective cancer therapy in adults with ALL.
Jae Park
Jae Park medical oncologist

“This is the longest follow-up study of people with ALL treated with CAR therapy,” says Jae Park, a medical oncologist at MSK and the principal investigator of the phase I trial. “It confirms the power of CAR T cells as an effective cancer therapy in adults with ALL. With the long follow-up, we were able to demonstrate for the first time that people with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity.”

Previous studies of CAR therapy in children and adults with ALL had shown impressive initial response rates, ranging from 70% to 90%. The follow-up data on these groups, however, is limited. Whether people treated with CAR T cells would continue to do well over time has been an open question.

The new results provide the first strong evidence that some people with an otherwise incurable cancer can experience lasting benefits extending to five years or more after receiving a single infusion of CAR T cells. The results also point to specific factors that may influence how well people do on the treatment.

“Among all of the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy,” Dr. Park says. “Our data suggest that we should give CAR therapy when the disease volume is small to achieve the greatest long-term efficacy and lowest toxicity.”

Ultimately, he says, it may make sense for people to receive CAR T cell therapy as a frontline treatment, rather than after other options have failed. 

A Powerful Treatment with Serious Potential Side Effects

Doctors and patients alike are excited about CAR therapy because it has proven to be a lifesaving option for very sick people who otherwise would have died from their disease. More than a thousand people in the United States alone have received the immune-based treatment, despite the sometimes severe side effects that can come from supercharging immune cells and releasing them into the body.

The main potential complication of CAR therapy is cytokine release syndrome (CRS). This powerful surge of immune activity can overwhelm the body’s organs and lead to death. Caring for people with CRS requires enormous skill and clinical expertise.

Another potential complication is neurotoxicity, including a dangerous swelling of the brain called cerebral edema. Some CAR trials have been stopped early because there were deaths from cerebral edema. None of these deaths occurred at MSK.

Strikingly, about 50% of people in the low-disease category were still alive and well after five years. Doctors speculate that they may be cured.

The results of this study provide important lessons for limiting and managing these side effects. They further show that CAR therapy provides a potential cure for a group of people — adults with relapsed ALL — for whom no FDA-approved CAR T cell treatment exists.

“This study represents the culmination of 20 years of research at MSK,” says Michel Sadelain, Director of the Center for Cell Engineering at MSK and lead author of the study. “These data strongly support the use of this CAR therapy for adults with relapsed ALL, and predict better outcomes when used earlier in the course of the disease.”

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Study Details

Patients enrolled on this trial received a single infusion of 19-28z CAR T cells manufactured at MSK. Each person’s T cells were isolated from their blood and exposed to a harmless viral vector that inserted the 19-28z CAR gene. The engineered CAR T cells were grown and multiplied in the lab and then infused back into the patient.

Everyone on the study had received multiple previous chemotherapy treatments and either had relapsed or was resistant to further chemotherapy. The rate of complete remission — meaning a leukemia-free state — was 83% (44 people). The overall rate of severe CRS was 26% (14 people), including one death. The rate of severe neurotoxicity was 42% (22 people). There were no cases of fatal neurotoxicity or cerebral edema on the trial.

Some people on the study went on to have a stem cell transplant. Receiving this additional treatment did not correlate with a better outcome.

The analysis of factors affecting the outcome of treatment was retrospective in nature and needs to be confirmed in a prospective trial. MSK investigators hope to open such a trial soon.

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About CAR T Cell Therapy

The CAR T cells used in this study are built to target a molecule called CD19. This marker is found on the surface of normal and cancerous B cells. MSK scientists were the first to show that CD19 is an optimal target for CAR therapy and played a pioneering role in developing CAR therapy. MSK’s CD19 CAR T therapy received a Breakthrough Therapy Designation from the FDA in 2014.

Two commercial CAR T cell therapies are currently approved for use in people: tisagenlecleucel (Kymriah®) for children and young adults with ALL and axicabtagene ciloleucel (Yescarta®) for adults with non-Hodgkin lymphoma.

There is no FDA-approved CAR T cell therapy for adults with ALL.

Car Cell Therapy
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Explore how MSK scientists and clinicians are using an immunotherapy called chimeric antigen receptor (CAR) T cell therapy to beat cancer.
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This work was supported by the National Institutes of Health, the Carson Family Charitable Trust, the Emerald Foundation, the Mr. and Mrs. Goodwyn Commonwealth Fund, the Terry Fox Run for Cancer Research organized by the Canadian Association of New York, Kate’s Team, the William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at MSK, Juno Therapeutics, and the Lake Road Foundation.

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Comments

My son has Chronic Myelogenous Leukaemia and has been an MSKCC patient since diagnosis aged 22 months. Does CAR T therapy hold any promise for CML patients? Thanks.

Dear John, we're very sorry to hear about your son's diagnosis. MSK doesn't currently have any trials looking at CAR T for CML. We recommend that you discuss the possibility of other trials with your son's healthcare team. Thank you for your comment, and best wishes to you.

The article above says hat this treatment was used in adults with ALL. What was the age range of the patients. This is important to know since the Kymriah treatment is for people up to age 25. There are many of us with B cell ALL who are much older than 25. I was 69 when diagnosed.

Dear Nancy,
The median age of patients in this study was 44, with a range of 23 to 74.
Thank you for your comment.

My 70-year old wife has aggressive follicular lymphoma (relapsed within months of completing 6 cycles of both R-CHOP and BR). She received an NIH CAR-T infusion on March 2, 2016 and is in complete remission. Her only remaining side effect is low immunoglobulins for which she received an IVIG infusion every 4 months (when her IgG drops below 400). What is your experience for how long someone like my wife is likely to remain in complete remission?

Dear William, we're glad to hear that your wife is doing well with her current treatment. We recommend that you discuss long-term prognosis with her medical team. Thank you for your comment, and best wishes to you.

I am looking for car T cell therapy for my husband that has advanced prostate cancer. Are you offering clinical trials for prostate cancer?

Dear Janet, we're sorry to hear about your husband's diagnosis. We do not have any trials for prostate cancer using CAR T cells, but we do have a number of other trials for prostate cancer. If your husband is interested in coming to MSK for a consultation 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, and best wishes to both of you.

Has CAR T been used to treat HCL?

Dear Anne, we sent your question to Dr. Park. He replied that he is not aware of any specific trials. However, hairy cell leukemias do express the same target that CD19 CAR T cells go after, so they theoretically can be used for treatment of HCL. We have a “basket trial" of CD19 CAR T cells, IRB#16-1570, for which patients with hairy cell leukemia may be eligible, even though it is not listed in the criteria for the trial. If you are interested in making an appointment at MSK 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, and best wishes to you.

My friend is in his mid 50s with AML. He has responded to initial chemotherapy and is currently receiving his 2nd chemotherapy session - consolidation therapy. He does not want bone marrow transplant. I am thinking of referring him to Sloan Kettering for possible CAR T therapy. Do you currently have clinical trial or the like for AML?

We're sorry to hear about your friend's diagnosis. If he would like to come to MSK for a consultation and to learn about clinical trial and other treatment options, he 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 and your friend.

My brother has Primary Refractory B-Cell ALL which was confirmed yesterday. He is 41 years old and was always in great shape. Currently under consideration for Blincyto and Besponsa but don't know if they will work for long. Can he be considered under Dr. Park's CAR T adult trial? He seems to fit well in the inclusion/exclusion criteria. Please help.

Dear Chet, we're very sorry to hear about your brother's diagnosis. If he would like to come to MSK to speak with one of our specialists and find out about clinical trials, he 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 both of you.

Are there any car t treatments or trials for t cell lymphoma
Thanks

Dear Boruch, the CAR T therapy that is currently approved is for B cell lymphomas that express the CD19 protein, as well as certain leukemias. There are not currently any CAR T trials at MSK for T cell lymphoma. We do have trials using other immunotherapies for T cell lymphomas. To learn more you can go to this link: https://www.mskcc.org/cancer-care/types/lymphoma/clinical-trials

Thank you for your comment, and best wishes to you.

My dad is a rectal cancer patient of Dr. Guillem. The cancer was removed in the week of 2017. This past week, two spots showed up on his liver. I have been reading about Amored CAR-T therapy for solid tumors. Is there a trial going on for CAR-T in relation to rectal cancer? If so, who can I contact? Thank you!

Dear John, we're sorry to hear about your father's recurrence. We don't currently have any CAR T trials for rectal cancer, but we do have a number of trials for rectal cancer, including some that use other forms of immunotherapy. We suggest that you and your father discuss this with Dr. Guillem. Thank you for your comment and best wishes to both of you.

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