I just saw a couple of things with regard to CAR T cell therapy for myeloma. Unfortunately this article is not available, but the abstract notes something that has been mentioned multiple times with regard to potential CAR T cell therapy for myeloma - there is not an obvious target that is not also expressed on normal cells.
Abstract:
Multiple myeloma is a haematologic malignancy characterized by the expansion of monoclonal plasma cells in the bone marrow. It is associated with serum or urine monoclonal protein and organ damage including renal failure, anaemia, hypercalcaemia and bone lesions. Despite recent improvements multiple myeloma still remains an incurable disease. Previous studies have shown that the adoptive transfer of autologous T-cells modified to express chimeric antigen receptors (CAR) is effective in cases of acute and chronic lymphoid leukaemia. However, the adjustment of CAR-T-cell therapy to multiple myeloma is hindered by the scarcity of antigens specific to the tumour plasma cells. Most candidate targets are shared by healthy tissues, and entail high risks of toxicity. Therefore several strategies have been proposed to regulate CAR-T-cell function as well as to enhance CAR-T-cell specificity against tumour cells. In this article we summarize the surface markers that have been investigated as targets to eliminate multiple myeloma plasma cells and the MM-specific CARs that have been developed to date. Then we describe the different CAR-T-cell designs that could be applied in the case of multiple myeloma to circumvent current problems of toxicity."
Reference:
Martínez-Cingolani, C. et al., “Development of chimeric antigen receptors for multiple myeloma” in the Biochemical Society Transactions, April 15, 2016 (abstract)
I saw an update about presentations at a scientific meeting with updates on the CAR T trials mentioned earlier in the thread. In the BCMA trial at the NIH, the patient with the stringent CR relapsed in 17 weeks. One of the 12 patients that achieved a VGPR remains in remission at 26 weeks. With regard to the CTL019 trial discussed in this article;
"CAR T-Cell Therapy For Multiple Myeloma: Promising Signs Of Efficacy (ASCO 2015)", The Myeloma Beacon, June 4, 2015
If I heard correctly there is also one patient in VGPR that has not relapsed. All others have relapsed. This really shows the difficulty in finding a good target for immunotherapy for myeloma.
Forums
Re: CAR T-cell therapy for multiple myeloma
There's been some disappointing news with regard to CAR T-cell therapy. The news broke Thursday and was reported widely then and yesterday. Here's what the New York Times wrote about it:
"Three patients in a study testing the use of genetically engineered cells as a treatment for cancer have died from swelling in the brain, dealing a setback to one of the most exciting pursuits in oncology.
Juno Therapeutics, the company conducting the clinical trial, said on Thursday that the Food and Drug Administration had temporarily halted the study.
The deaths were “difficult and humbling for everyone involved,” Hans Bishop, the company’s chief executive, said in a conference call with securities analysts."
Juno has been discussing that they thought the addition of fludarabine was the problem. I did see an interesting article with regard to that theory. Fludarabine has been used for decades in allo transplant and I used a high dose and had no problems with regard to it.
"The chemo fludarabine was used in the study to complete a round of lymphodepletion, eliminating diseased B cells to assist the newly inserted CAR-T cells to repopulate and do their work. It’s the same type of conditioning patients receive for hematopoeitic stem cell transplants. It’s also a procedure used in other CAR-T trials, with no history of cerebral edemas. And there’s no record of fludarabine being linked to cerebral edemas, [Sally Church] writes ...
[Church] asked a group of hematologists what they knew of a connection. Response: Nothing. And she queried Dr. Stephan Grupp (CHOP), who “probably treated more pediatric ALL [acute lymphocytic leukemia] patients with CAR T cell therapy than anyone”:
“We have not seen significant cerebral edema in any of our pediatric ALL patients on the CHOP/Penn study treated with CTL019, many of whom received fludarabine. CNS-related side effects have been seen, including confusion, aphasia and seizures in a small number of patients, but these effects have all resolved. Obviously, it is always hard to attribute toxicity to the chemo vs. the CAR T cells when both are given around the same time, but we believe the self-limited CNS side effects we have reported are more likely to be due to the T cells.”
Both Juno as well as rival Kite Pharma use CD-28 as a co-stimulation domain, she adds. Penn/CHOP/Novartis use 4–1BB. There are differences in patient responses, but no cases of cerebral edema have been reported by Kite so far, though Kite has had the same limited CNS issues that Juno has reported."
"Three patients in a study testing the use of genetically engineered cells as a treatment for cancer have died from swelling in the brain, dealing a setback to one of the most exciting pursuits in oncology.
Juno Therapeutics, the company conducting the clinical trial, said on Thursday that the Food and Drug Administration had temporarily halted the study.
The deaths were “difficult and humbling for everyone involved,” Hans Bishop, the company’s chief executive, said in a conference call with securities analysts."
Juno has been discussing that they thought the addition of fludarabine was the problem. I did see an interesting article with regard to that theory. Fludarabine has been used for decades in allo transplant and I used a high dose and had no problems with regard to it.
"The chemo fludarabine was used in the study to complete a round of lymphodepletion, eliminating diseased B cells to assist the newly inserted CAR-T cells to repopulate and do their work. It’s the same type of conditioning patients receive for hematopoeitic stem cell transplants. It’s also a procedure used in other CAR-T trials, with no history of cerebral edemas. And there’s no record of fludarabine being linked to cerebral edemas, [Sally Church] writes ...
[Church] asked a group of hematologists what they knew of a connection. Response: Nothing. And she queried Dr. Stephan Grupp (CHOP), who “probably treated more pediatric ALL [acute lymphocytic leukemia] patients with CAR T cell therapy than anyone”:
“We have not seen significant cerebral edema in any of our pediatric ALL patients on the CHOP/Penn study treated with CTL019, many of whom received fludarabine. CNS-related side effects have been seen, including confusion, aphasia and seizures in a small number of patients, but these effects have all resolved. Obviously, it is always hard to attribute toxicity to the chemo vs. the CAR T cells when both are given around the same time, but we believe the self-limited CNS side effects we have reported are more likely to be due to the T cells.”
Both Juno as well as rival Kite Pharma use CD-28 as a co-stimulation domain, she adds. Penn/CHOP/Novartis use 4–1BB. There are differences in patient responses, but no cases of cerebral edema have been reported by Kite so far, though Kite has had the same limited CNS issues that Juno has reported."
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Mark11
Re: CAR T-cell therapy for multiple myeloma
Thank you for continuing to observe and post on this topic regularly, Mark11. It's been very helpful reading this thread. I saw that story and various reports last week and it's definitely disappointing. So sad for the families who were very hopeful about a new experimental therapy possibly getting their loved ones back on track.
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texgal79 - Who do you know with myeloma?: Husband
- When were you/they diagnosed?: 2016
- Age at diagnosis: 43
Re: CAR T-cell therapy for multiple myeloma
Yes, thank you Mark for posting the story about CAR-T cell immunotherapy. I met one of the patients on the clinical trial last year and he did not survive that either. That was really depressing. I hope that the other patients do better, though.
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
Re: CAR T-cell therapy for multiple myeloma
I read yesterday the FDA has now cleared Juno to resume Phase II of the clinical trial:
http://www.bloomberg.com/news/articles/2016-07-12/juno-soars-after-u-s-regulators-allow-leukemia-study-to-resume
So that is great news!
My myeloma specialist mentioned this may be used in the next couple of years for myeloma too. She is currently assisting with researching it.
Maybe, just maybe, there will be a cure in our lifetime!
Best wishes to all.
Rhonda
http://www.bloomberg.com/news/articles/2016-07-12/juno-soars-after-u-s-regulators-allow-leukemia-study-to-resume
So that is great news!
My myeloma specialist mentioned this may be used in the next couple of years for myeloma too. She is currently assisting with researching it.
Maybe, just maybe, there will be a cure in our lifetime!
Best wishes to all.
Rhonda
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Rhonda - Who do you know with myeloma?: myself
- When were you/they diagnosed?: September 2014
- Age at diagnosis: 54
Re: CAR T-cell therapy for multiple myeloma
Thank you TexGal, Nancy S., and Rhonda.
Believe it or not, I think myeloma is the first disease that has a trial using CAR T-cell therapy in the upfront setting. Here is a link to a trial using a CD19 CAR T-cell therapy after an auto for newly diagnosed, high-risk patients.
"CART-19 Post-ASCT for Multiple Myeloma" (information at clinicaltrials.gov)
I am really looking forward to seeing the results of this study. If I am reading correctly, it is Revlimid, Velcade, and dexamethasone followed by an autologous stem cell transplant with a CAR T-cell infusion followed by Revlimid maintenance. Will be interesting to see how much benefit there is to a standard treatment protocol.
Believe it or not, I think myeloma is the first disease that has a trial using CAR T-cell therapy in the upfront setting. Here is a link to a trial using a CD19 CAR T-cell therapy after an auto for newly diagnosed, high-risk patients.
"CART-19 Post-ASCT for Multiple Myeloma" (information at clinicaltrials.gov)
I am really looking forward to seeing the results of this study. If I am reading correctly, it is Revlimid, Velcade, and dexamethasone followed by an autologous stem cell transplant with a CAR T-cell infusion followed by Revlimid maintenance. Will be interesting to see how much benefit there is to a standard treatment protocol.
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Mark11
Re: CAR T-cell therapy for multiple myeloma
Here is a link to an abstract with initial results of the BCMA CAR T-cell trial at the NIH.
Abbas Ali, S., et al,"T cells expressing an anti-B-cell-maturation-antigen chimeric antigen receptor cause remissions of multiple myeloma," Blood, July 2016 (abstract)
Abstract:
Therapies with novel mechanisms of action are needed for multiple myeloma. B-cell maturation antigen (BCMA) is expressed by most cases of multiple myeloma. We conducted the first-in-humans clinical trial of chimeric antigen receptor (CAR) T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells on this dose-escalation trial.
Among the 6 patients treated on the lowest two dose levels, limited anti-myeloma activity and mild toxicity occurred. On the third dose level, one patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9×106 CAR+ T cells/kg bodyweight.
Before treatment, the first patient on the fourth dose level had chemotherapy-resistant multiple myeloma making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's multiple myeloma entered a stringent complete remission that lasted for 17 weeks before relapse.
The second patient on the fourth dose level had chemotherapy-resistant multiple myeloma making up 80% of bone marrow cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T-cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. This patient is in an ongoing very good partial remission. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients also had prolonged cytopenias.
Our findings demonstrate powerful anti-myeloma activity of CAR-BCMA T cells.
Here are some supplemental data from the study. The data include the treatment histories of the patients in the study. I really hope the study in the previous post shows benefit so patients can avoid all those lines of therapy.
Abbas Ali, S., et al,"T cells expressing an anti-B-cell-maturation-antigen chimeric antigen receptor cause remissions of multiple myeloma," Blood, July 2016 (abstract)
Abstract:
Therapies with novel mechanisms of action are needed for multiple myeloma. B-cell maturation antigen (BCMA) is expressed by most cases of multiple myeloma. We conducted the first-in-humans clinical trial of chimeric antigen receptor (CAR) T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells on this dose-escalation trial.
Among the 6 patients treated on the lowest two dose levels, limited anti-myeloma activity and mild toxicity occurred. On the third dose level, one patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9×106 CAR+ T cells/kg bodyweight.
Before treatment, the first patient on the fourth dose level had chemotherapy-resistant multiple myeloma making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's multiple myeloma entered a stringent complete remission that lasted for 17 weeks before relapse.
The second patient on the fourth dose level had chemotherapy-resistant multiple myeloma making up 80% of bone marrow cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T-cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. This patient is in an ongoing very good partial remission. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients also had prolonged cytopenias.
Our findings demonstrate powerful anti-myeloma activity of CAR-BCMA T cells.
Here are some supplemental data from the study. The data include the treatment histories of the patients in the study. I really hope the study in the previous post shows benefit so patients can avoid all those lines of therapy.
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Mark11
Re: CAR T-cell therapy for multiple myeloma
Mark11,
Thank you for posting the clinical trial that is starting at Penn and the results of the NIH trial. It helps to know what is going on with the various CAR trials and their different approaches. I knew that Penn would be starting their next CAR trial with myeloma patients, but didn't know the specifics.
Dr. Garfall is a relatively new myeloma specialist and deserves lots of attention. It appears that he is a rising star in the myeloma community. I think that we will be hearing more and more from him in the years to come.
Penn also is going to be part of the CRISPR trial that includes people with myeloma.
So much that is happening and maybe good progress towards improving our outcomes with myeloma.
Nancy in Phila
Thank you for posting the clinical trial that is starting at Penn and the results of the NIH trial. It helps to know what is going on with the various CAR trials and their different approaches. I knew that Penn would be starting their next CAR trial with myeloma patients, but didn't know the specifics.
Dr. Garfall is a relatively new myeloma specialist and deserves lots of attention. It appears that he is a rising star in the myeloma community. I think that we will be hearing more and more from him in the years to come.
Penn also is going to be part of the CRISPR trial that includes people with myeloma.
So much that is happening and maybe good progress towards improving our outcomes with myeloma.
Nancy in Phila
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NStewart - Name: Nancy Stewart
- Who do you know with myeloma?: self
- When were you/they diagnosed?: 3/08
- Age at diagnosis: 60
Re: CAR T-cell therapy for multiple myeloma
Mark11,
After all your research into CAR-T, which target do you think holds the most promise?
Tracy
After all your research into CAR-T, which target do you think holds the most promise?
Tracy
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Tracy J - Name: Tracy Jalbuena
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: 2014
- Age at diagnosis: 42
Re: CAR T-cell therapy for multiple myeloma
I just wanted to echo Nancy's sentiment and offer condolences for the leukemia patients that passed away on the CAR-T cell leukemia trial (apparently due to the bad interaction with the fludaribine). As a rule, clinical trials involve some degree of risk. It is required and appropriate that patients on clinical trial have their privacy protected. We do not know how good or poor was their prognosis. Maybe they were at or near the end of their journey, anyway, maybe not. I am reasonably sure that they must have been hopeful to get good results from the CAR-T therapy, with all of its promise and hope. Clearly, it was very disappointing for the patients and their families in that regard. I believe that people who step up and participate in clinical trials are heroes.
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JPC - Name: JPC
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