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Re: CAR T-cell therapy for multiple myeloma
I, too, would like to offer my condolences to the families of those who participated in the CAR-T trial. It is heartbreaking to know that these trailblazers gave their lives to further the research into treatments for myeloma.
Re: CAR T-cell therapy for multiple myeloma
Hi TracyJ,
This question is really over my "pay grade". It likely depends on what you want the cells to do. If you are a relapsed patient who is looking to get to remission, so far the evidence would appear to favor BCMA. We can see how well anti-CD38 antibodies do, but I for one would be hesitant to use a CAR T-cell directed at CD38 since CD38 is expressed on many normal cells. As far as CD38 is concerned, I am curious if they will look to construct a BiTE (Bi-specific T-cell engager) with CD38. For those not familiar, you could look at a BiTE as a therapy that is in-between an antibody and a CAR T-cell. There is a BiTE that is FDA approved for relapsed acute lymphoblastic leukemia called Blincyto (blinatumomab).
With respect to a CAR T cell being a potential cure / providing long-term drug-free remissions with good quality of life for myeloma patients, until they know what the underlying cause of relapse is, it will be difficult for any "targeted" therapy to accomplish that, especially for relapsed patients. Targeted therapies help, a good example is adding Rituximab to CHOP increases the cure rate for certain lymphomas, but by itself Rituximab is not a cure.
Mark
This question is really over my "pay grade". It likely depends on what you want the cells to do. If you are a relapsed patient who is looking to get to remission, so far the evidence would appear to favor BCMA. We can see how well anti-CD38 antibodies do, but I for one would be hesitant to use a CAR T-cell directed at CD38 since CD38 is expressed on many normal cells. As far as CD38 is concerned, I am curious if they will look to construct a BiTE (Bi-specific T-cell engager) with CD38. For those not familiar, you could look at a BiTE as a therapy that is in-between an antibody and a CAR T-cell. There is a BiTE that is FDA approved for relapsed acute lymphoblastic leukemia called Blincyto (blinatumomab).
With respect to a CAR T cell being a potential cure / providing long-term drug-free remissions with good quality of life for myeloma patients, until they know what the underlying cause of relapse is, it will be difficult for any "targeted" therapy to accomplish that, especially for relapsed patients. Targeted therapies help, a good example is adding Rituximab to CHOP increases the cure rate for certain lymphomas, but by itself Rituximab is not a cure.
Mark
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Mark11
Re: CAR T-cell therapy for multiple myeloma
Hi Nancy in Phila.,
Hope your air conditioning is working well!
I could not agree more with this statement you made:
As a patient who used immunotherapy as the backbone of my upfront therapy, it seems clear to me that Dr. Garfall is "on the right track". The trial that is just starting for newly diagnosed patients clearly shows that Dr. Garfall has learned the important lessons from allogeneic transplantation, which is that immunotherapy for blood cancer patients is most effective when done in first complete response (or as close as you can get) and when it is used with high-dose chemotherapy.
The other point that I think is important is that therapies that are good at maintaining remissions may not necessarily show a great deal of activity on active disease in relapsed patients. In my opinion, the CD19-targeted CAR T-cell therapy CTL019 (tisagenlecleucel-T) did not show much activity on cells that we typically monitor, but that does not mean that it cannot be beneficial in helping keep a patient there. Allogeneic transplantation is the classic example of a therapy that does not do very well on patients with relapsed, / active disease, but is excellent consolidation / maintenance therapy.
Currently in myeloma the therapies are good at getting most newly diagnosed patients to VGPR to an MRD negative CR, but the responses are not typically durable, meaning that the current therapies are not very effective as consolidation and maintenance. The only way to find out if a CD19 CAR T cell will help maintain patients remissions is a trial like this one.
As a general comment I do think younger doctors will lead us closer to a cure, as opposed to the current group of "myeloma thought leaders". While they have made great strides in the last decade, myeloma still lags far behind many other blood cancers. Few myeloma patients are cured, and myeloma is not a chronic blood cancer like CML (chronic myelogenous leukemia). I have met many patients that appear to be cured of blood cancer and live with a good quality of life. Unfortunately few of them were diagnosed with myeloma.
Mark
Hope your air conditioning is working well!
I could not agree more with this statement you made:
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.
As a patient who used immunotherapy as the backbone of my upfront therapy, it seems clear to me that Dr. Garfall is "on the right track". The trial that is just starting for newly diagnosed patients clearly shows that Dr. Garfall has learned the important lessons from allogeneic transplantation, which is that immunotherapy for blood cancer patients is most effective when done in first complete response (or as close as you can get) and when it is used with high-dose chemotherapy.
The other point that I think is important is that therapies that are good at maintaining remissions may not necessarily show a great deal of activity on active disease in relapsed patients. In my opinion, the CD19-targeted CAR T-cell therapy CTL019 (tisagenlecleucel-T) did not show much activity on cells that we typically monitor, but that does not mean that it cannot be beneficial in helping keep a patient there. Allogeneic transplantation is the classic example of a therapy that does not do very well on patients with relapsed, / active disease, but is excellent consolidation / maintenance therapy.
Currently in myeloma the therapies are good at getting most newly diagnosed patients to VGPR to an MRD negative CR, but the responses are not typically durable, meaning that the current therapies are not very effective as consolidation and maintenance. The only way to find out if a CD19 CAR T cell will help maintain patients remissions is a trial like this one.
As a general comment I do think younger doctors will lead us closer to a cure, as opposed to the current group of "myeloma thought leaders". While they have made great strides in the last decade, myeloma still lags far behind many other blood cancers. Few myeloma patients are cured, and myeloma is not a chronic blood cancer like CML (chronic myelogenous leukemia). I have met many patients that appear to be cured of blood cancer and live with a good quality of life. Unfortunately few of them were diagnosed with myeloma.
Mark
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Mark11
Re: CAR T-cell therapy for multiple myeloma
Here are the early results of a CAR T-cell study targeting a light chain.
Ramos, C.A., "Clinical responses with T lymphocytes targeting malignancy-associated κ light chains", Journal of Clinical Investigation, June 6, 2016 (full text of article)
Abstract
BACKGROUND - Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment.
METHODS - We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ+ non-Hodgkin lymphoma / chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma with autologous T cells genetically modified to express κ.CAR (κ.CARTs). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 × 108 to 2 × 108 κ.CARTs/m2). No other lymphodepletion was used.
RESULTS - κ.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with multiple myeloma, 4 had stable disease lasting 2-17 months. No toxicities attributable to κ.CARTs were observed.
CONCLUSION - κ.CART infusion is feasible and safe and can lead to complete clinical responses.
Ramos, C.A., "Clinical responses with T lymphocytes targeting malignancy-associated κ light chains", Journal of Clinical Investigation, June 6, 2016 (full text of article)
Abstract
BACKGROUND - Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment.
METHODS - We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ+ non-Hodgkin lymphoma / chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma with autologous T cells genetically modified to express κ.CAR (κ.CARTs). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 × 108 to 2 × 108 κ.CARTs/m2). No other lymphodepletion was used.
RESULTS - κ.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with multiple myeloma, 4 had stable disease lasting 2-17 months. No toxicities attributable to κ.CARTs were observed.
CONCLUSION - κ.CART infusion is feasible and safe and can lead to complete clinical responses.
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Mark11
Re: CAR T-cell therapy for multiple myeloma
For those interested in the subject of immunotherapy, there was some news yesterday in the business press with regard to Novartis disbanding its cell and gene therapy unit. They are still going to work on getting CTL019 to market with the University of Pennsylvania. There are a lot of different views in the business press about what this means, if anything, for the future of CAR T cells as a potential therapy:
"Scoop: Novartis disbands its pioneering cell and gene therapy unit," Endpoints, Aug 31, 2016 (link to article)
"Novartis Closing Cell Therapy Unit; CAR-T Stocks Tumble," Investors Business Daily, Aug 31, 2016 (link to article)
"What Signal Is Novartis AG (NYSE:NVS) Sending Out With Its Cell Therapy Move?", marketexclusive.com, Sep 1, 2016 (link to full article)
"Scoop: Novartis disbands its pioneering cell and gene therapy unit," Endpoints, Aug 31, 2016 (link to article)
"Novartis Closing Cell Therapy Unit; CAR-T Stocks Tumble," Investors Business Daily, Aug 31, 2016 (link to article)
"What Signal Is Novartis AG (NYSE:NVS) Sending Out With Its Cell Therapy Move?", marketexclusive.com, Sep 1, 2016 (link to full article)
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Mark11
Re: CAR T-cell therapy for multiple myeloma
Interesting article on the front page of today's Washington Post regarding the use of engineered T-cells to treat leukemia in children. Talks about how leukemia can change over time so people relapse.
"This 8-year-old is free of cancer – for now – after a ‘breakthrough’ treatment," The Washington Post, Oct 4, 2016 (link to full text of article)
Excerpt from the article:
By the time 8-year-old Ava Christianson got to the National Institutes of Health this summer, she had lost several grueling rounds to leukemia and was bracing for the next one ...
But Ava was fortunate in one respect. Discoveries in the burgeoning field of immunotherapy are offering lifelines to desperate patients who previously had none. “Five years ago,” said her mother, Bethany Christianson, “our doctor would have just had to tell us to go home.”
Instead, in a five-minute procedure at the NIH Clinical Center in late July, the freckle-face girl got another chance to beat the acute lymphoblastic leukemia (ALL) that has stalked her since age 4. She was infused with 30 million of her own T cells, a key part of the immune system, that had been genetically modified to track down and kill her cancer like a pack of crazed dogs.
Ava’s treatment, called CAR T-cell therapy, is one of the new immunotherapies that attempt to rally the body’s own defenses to fight malignancies. Unlike other cancer advances, it is being tested widely in children because of its stunning effectiveness in ALL, the most common pediatric cancer. In early-stage trials, many patients who had repeatedly relapsed saw their leukemia disappear. Some remain cancer-free.
Yet big questions surround the therapy, and many scientists are urging caution. “There’s very real promise with this approach, but the immune system is complicated,” said Terry Fry, the National Cancer Institute (NCI) scientist who is running Ava’s trial. “There’s a lot that still needs to be worked out.”
Complications can be lethal; one clinical trial was briefly halted in July after three young adults died of brain swelling. It is also far from clear that such a personalized approach – possibly costing hundreds of thousands of dollars – is economically viable on a large scale or will produce the lasting remissions that everyone hopes to see.
Lyn
"This 8-year-old is free of cancer – for now – after a ‘breakthrough’ treatment," The Washington Post, Oct 4, 2016 (link to full text of article)
Excerpt from the article:
By the time 8-year-old Ava Christianson got to the National Institutes of Health this summer, she had lost several grueling rounds to leukemia and was bracing for the next one ...
But Ava was fortunate in one respect. Discoveries in the burgeoning field of immunotherapy are offering lifelines to desperate patients who previously had none. “Five years ago,” said her mother, Bethany Christianson, “our doctor would have just had to tell us to go home.”
Instead, in a five-minute procedure at the NIH Clinical Center in late July, the freckle-face girl got another chance to beat the acute lymphoblastic leukemia (ALL) that has stalked her since age 4. She was infused with 30 million of her own T cells, a key part of the immune system, that had been genetically modified to track down and kill her cancer like a pack of crazed dogs.
Ava’s treatment, called CAR T-cell therapy, is one of the new immunotherapies that attempt to rally the body’s own defenses to fight malignancies. Unlike other cancer advances, it is being tested widely in children because of its stunning effectiveness in ALL, the most common pediatric cancer. In early-stage trials, many patients who had repeatedly relapsed saw their leukemia disappear. Some remain cancer-free.
Yet big questions surround the therapy, and many scientists are urging caution. “There’s very real promise with this approach, but the immune system is complicated,” said Terry Fry, the National Cancer Institute (NCI) scientist who is running Ava’s trial. “There’s a lot that still needs to be worked out.”
Complications can be lethal; one clinical trial was briefly halted in July after three young adults died of brain swelling. It is also far from clear that such a personalized approach – possibly costing hundreds of thousands of dollars – is economically viable on a large scale or will produce the lasting remissions that everyone hopes to see.
Lyn
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Christa's Mom - Name: Christa's Mom
- Who do you know with myeloma?: Husband
- When were you/they diagnosed?: September, 2010
- Age at diagnosis: 53
Re: CAR T-cell therapy for multiple myeloma
My husband is in line to go on a CAR-T study at Mayo. They expect him to be in by late December. He's thrilled. I have to admit I'm pretty worried about it.
Last edited by rumnting on Fri Oct 07, 2016 12:04 pm, edited 1 time in total.
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rumnting - Who do you know with myeloma?: husband
- When were you/they diagnosed?: 4/9/11
- Age at diagnosis: 54
Re: CAR T-cell therapy for multiple myeloma
Rumnting,
That's pretty exciting news, but I can also understand your angst. Do you know which cell marker this study is going to target?
Wishing your hubby all the best and I hope that you can update us from time to time during the journey.
That's pretty exciting news, but I can also understand your angst. Do you know which cell marker this study is going to target?
Wishing your hubby all the best and I hope that you can update us from time to time during the journey.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: CAR T-cell therapy for multiple myeloma
Rumnting:
I'll echo Multibilly. This is an exciting new therapy, and I wish you and your husband the very best. I can't blame you for being worried, but from what I've read, they are pretty good at managing the side effects of the treatment, and they're getting better at it all the time.
I'll echo Multibilly. This is an exciting new therapy, and I wish you and your husband the very best. I can't blame you for being worried, but from what I've read, they are pretty good at managing the side effects of the treatment, and they're getting better at it all the time.
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Mike F - Name: Mike F
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: May 18, 2012
- Age at diagnosis: 53
Re: CAR T-cell therapy for multiple myeloma
Multibilly,
The cell marker for this CAR T-cell therapy is BCMA.
The cell marker for this CAR T-cell therapy is BCMA.
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rumnting - Who do you know with myeloma?: husband
- When were you/they diagnosed?: 4/9/11
- Age at diagnosis: 54
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