Does anyone know of any research out there where a patient's own stem cells are treated to make them recognize the myeloma cells as defective and consequently, fight the disease? I'm thinking that allo transplants are sometimes so effective because the new immune system recognizes the myeloma cells as bad and works to eliminate these cells, when your own immune system will not, but carries some major risks.
Thanks,
Sandy
Forums
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SandyC63 - Name: SandyC
- Who do you know with myeloma?: My Husband
- When were you/they diagnosed?: 2012
- Age at diagnosis: 51
Re: Treating collected stem cells to kill myeloma cells
Wouldn't that be the cat's meow? I'm not aware of any work being done along these lines, but somebody else may know differently.
I remain excited about the promise of a class of monoclonal antibodies that will be able to allow your existing immune cells to recognize the myeloma cells as deviants and then facilitate their death. So, instead of altering your good cells to fight the battle (as you propose), you are instead planting a flag on the deceptive myeloma cells (which essentially masquerade as healthy cells and also cheat a normal, programmed death). Your immune system can then recognize this flag on the myeloma cells and target them for execution. A different approach, but clever nonetheless.
Perhaps someone here who's more knowledgeable will know of any research along the lines you suggest.
I remain excited about the promise of a class of monoclonal antibodies that will be able to allow your existing immune cells to recognize the myeloma cells as deviants and then facilitate their death. So, instead of altering your good cells to fight the battle (as you propose), you are instead planting a flag on the deceptive myeloma cells (which essentially masquerade as healthy cells and also cheat a normal, programmed death). Your immune system can then recognize this flag on the myeloma cells and target them for execution. A different approach, but clever nonetheless.
Perhaps someone here who's more knowledgeable will know of any research along the lines you suggest.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Treating collected stem cells to kill myeloma cells
Sandy,
Follow the link below to a prior myeloma beacon post where there is a discussion about something very simular to what you are asking about is being researched and has been done. The stem cells themselves are not treated but the mature immune cells are.
https://myelomabeacon.org/forum/t-cell-treatment-with-sct-for-myeloma-t2178.html
Follow the link below to a prior myeloma beacon post where there is a discussion about something very simular to what you are asking about is being researched and has been done. The stem cells themselves are not treated but the mature immune cells are.
https://myelomabeacon.org/forum/t-cell-treatment-with-sct-for-myeloma-t2178.html
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Eric Hofacket - Name: Eric H
- When were you/they diagnosed?: 01 April 2011
- Age at diagnosis: 44
Re: Treating collected stem cells to kill myeloma cells
I believe the University of Pennsylvania is at the forefront of using genetically engineered killer T Cells in blood cancers, including myeloma. Just google Dr. Carl June who is an amazing man on a mission to eradicate cancer. His work with CML, a type of leukemia, was reported on internationally two years ago.
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terryl1 - Name: Terry
- Who do you know with myeloma?: self
- When were you/they diagnosed?: August 10, 2011
- Age at diagnosis: 49
Re: Treating collected stem cells to kill myeloma cells
The above approach is fascinating and exciting. I'm truly happy for CLL patients...it's got to be giving many sufferers of that disease some good hope.
This technique got me to thinking if the new Crispr technique in the following article could also be used to re-engineer one's harvested cells en masse for the desired genetic change, and then reinfuse them back into the patient? Or, maybe you could even apply this technique in vivo to the desired cells without going through a cell harvest?
I think the Crispr technique described below is absolutely mind blowing. I'm still trying to get my head around the implications of this breakthrough.
http://www.independent.co.uk/news/science/exclusive-jawdropping-breakthrough-hailed-as-landmark-in-fight-against-hereditary-diseases-as-crispr-technique-heralds-genetic-revolution-8925295.html
This technique got me to thinking if the new Crispr technique in the following article could also be used to re-engineer one's harvested cells en masse for the desired genetic change, and then reinfuse them back into the patient? Or, maybe you could even apply this technique in vivo to the desired cells without going through a cell harvest?
I think the Crispr technique described below is absolutely mind blowing. I'm still trying to get my head around the implications of this breakthrough.
http://www.independent.co.uk/news/science/exclusive-jawdropping-breakthrough-hailed-as-landmark-in-fight-against-hereditary-diseases-as-crispr-technique-heralds-genetic-revolution-8925295.html
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Treating collected stem cells to kill myeloma cells
There are a couple of ideas floating around in this discussion which are similar, but not quite the same.
One idea is the original idea that was floated, which is killing leftover myeloma cells in harvested stem cells.
The other idea -- which, I believe, includes the research being done at Penn -- is using the harvested stem cells to create personalized anti-myeloma therapies. The goal of those therapies is not so much to kill off the leftover myeloma cells in the harvested stem cells, as it is to come up with personalized treatment which, when it's reintroduced into the patient's body with the harvested stem cells, acts as an additional therapy against myeloma.
As to the first concept, it (not surprisingly) has been looked at off and on during the last 25 years or so. The concept is known in medical circles as "ex vivo purging" (or sometimes "ex vivo depletion") of the stem cells.
This recent paper has an overview of some of the research that has been done on ex vivo purging in blood cancers,
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265224/
It includes this explanation of the evidence as to why ex vivo purging is likely to be beneficial in blood cancers where autologous transplantation is done:
"Despite the significant increase in use of autologous HCT for hematologic malignancies, disease relapse is a primary cause of death after transplant. Graft contamination is thought to be the chief reason for posttransplant relapse. This premise is supported by multiple lines of evidence. First, transplant of HSPC from syngeneic (identical twin) donors leads to lower incidences of disease relapse in patients with multiple myeloma, low-grade non-Hodgkin's lymphoma, AML, and ALL. Second, numerous reports show that transplanted autografts contain minimal residual disease (MRD) in a variety of patients with cancer. The level of MRD, detected by flow cytometry, immunohistochemistry, and molecular methods, directly correlated with risk of disease relapse and death. Whereas these lines of evidence show a strong correlation, direct proof of contaminated autografts through tracing studies are most compelling. Thus, the third line of evidence comes from gene marking studies. In these clinical studies, autologous HSPCs were genetically tagged and then transplanted. Relapsed disease was evaluated for the tag. In a variety of leukemias and cancers, the posttransplant relapsed disease contained the pretransplant tag. Together, these lines of evidence support the premise that contaminating cells within the autologous transplant graft can be the origin of relapsed disease after transplant."
One idea is the original idea that was floated, which is killing leftover myeloma cells in harvested stem cells.
The other idea -- which, I believe, includes the research being done at Penn -- is using the harvested stem cells to create personalized anti-myeloma therapies. The goal of those therapies is not so much to kill off the leftover myeloma cells in the harvested stem cells, as it is to come up with personalized treatment which, when it's reintroduced into the patient's body with the harvested stem cells, acts as an additional therapy against myeloma.
As to the first concept, it (not surprisingly) has been looked at off and on during the last 25 years or so. The concept is known in medical circles as "ex vivo purging" (or sometimes "ex vivo depletion") of the stem cells.
This recent paper has an overview of some of the research that has been done on ex vivo purging in blood cancers,
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265224/
It includes this explanation of the evidence as to why ex vivo purging is likely to be beneficial in blood cancers where autologous transplantation is done:
"Despite the significant increase in use of autologous HCT for hematologic malignancies, disease relapse is a primary cause of death after transplant. Graft contamination is thought to be the chief reason for posttransplant relapse. This premise is supported by multiple lines of evidence. First, transplant of HSPC from syngeneic (identical twin) donors leads to lower incidences of disease relapse in patients with multiple myeloma, low-grade non-Hodgkin's lymphoma, AML, and ALL. Second, numerous reports show that transplanted autografts contain minimal residual disease (MRD) in a variety of patients with cancer. The level of MRD, detected by flow cytometry, immunohistochemistry, and molecular methods, directly correlated with risk of disease relapse and death. Whereas these lines of evidence show a strong correlation, direct proof of contaminated autografts through tracing studies are most compelling. Thus, the third line of evidence comes from gene marking studies. In these clinical studies, autologous HSPCs were genetically tagged and then transplanted. Relapsed disease was evaluated for the tag. In a variety of leukemias and cancers, the posttransplant relapsed disease contained the pretransplant tag. Together, these lines of evidence support the premise that contaminating cells within the autologous transplant graft can be the origin of relapsed disease after transplant."
Re: Treating collected stem cells to kill myeloma cells
Dear all,
Purging autologous stem cells of myeloma has been tested in the past and produced disappointing results, although many of these studies are older. The thought is that the number of contaminating myeloma cells in the stem cell product are typically far lower than the number of residual myeloma cells left in the patient after treatment. As such, the numbers of cells left behind in the patient dictates when the disease will come back. Now that treatment is far better at producing high quality complete remissions and we have better techniques at measuring minimal residual disease, this is certainly an area worthy of revisiting.
Manipulation of the immune system to key it in to attack left behind myeloma is an exciting avenue of research. The approach being tested by Dr. June is starting to be investigated in the laboratory for a number of conditions, including myeloma. Hopefully we will have clinical trials in the near future to determine the feasibility and effectiveness of this approach. The monoclonal antibodiy therapies in development serve as a way of tagging myeloma cells and targeting them for destruction by the immune system. The anti-CD38 antibodies in clinical development look very promising in this regard (e.g. daratumumab) as does elotuzumab (when combined with Revlimid).
Lastly, a lot has been learned about how cancers in general evade destruction by the immune system and therapies directed at this problem are already approved for other cancers such as melanoma.
I suspect the emerging immunotherapeutics are going to make a big splash in myeloma in the years to come!
Pete V.
Purging autologous stem cells of myeloma has been tested in the past and produced disappointing results, although many of these studies are older. The thought is that the number of contaminating myeloma cells in the stem cell product are typically far lower than the number of residual myeloma cells left in the patient after treatment. As such, the numbers of cells left behind in the patient dictates when the disease will come back. Now that treatment is far better at producing high quality complete remissions and we have better techniques at measuring minimal residual disease, this is certainly an area worthy of revisiting.
Manipulation of the immune system to key it in to attack left behind myeloma is an exciting avenue of research. The approach being tested by Dr. June is starting to be investigated in the laboratory for a number of conditions, including myeloma. Hopefully we will have clinical trials in the near future to determine the feasibility and effectiveness of this approach. The monoclonal antibodiy therapies in development serve as a way of tagging myeloma cells and targeting them for destruction by the immune system. The anti-CD38 antibodies in clinical development look very promising in this regard (e.g. daratumumab) as does elotuzumab (when combined with Revlimid).
Lastly, a lot has been learned about how cancers in general evade destruction by the immune system and therapies directed at this problem are already approved for other cancers such as melanoma.
I suspect the emerging immunotherapeutics are going to make a big splash in myeloma in the years to come!
Pete V.
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Dr. Peter Voorhees - Name: Peter Voorhees, M.D.
Beacon Medical Advisor
Re: Treating collected stem cells to kill myeloma cells
Hi Dr. Voorhees - Thanks for the excellent response to this question. Do you really think the approach Dr. June is using is feasible for the long term on large groups of patients? From what I read in all the CLL patients the therapy worked for had all of their healthy B cells wiped out and the therapy continues to destroy them. That seems to be a significant form of extensive chronic GVHD. I had read this in Pubmed about myeloma.
"Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expand the possible indications for chimeric-antigen receptor (CAR)-T cells. B-cell maturation antigen (BCMA) is expressed only on mature B cells and plasma cells and promotes their survival. BCMA is a promising target for CAR-T cells in multiple myeloma."
http://www.ncbi.nlm.nih.gov/pubmed/23444214
Does this mean a myeloma patient would have no B cells or plasma cells? How would they get enough IVIG to give to a large number of patients since this therapy does not allow them to have healthy functioning immune systems if the therapy "works"?
I am a "hard grader" with respect to therapy since my Immunology Panel is all in the normal range 2.5 years after my allo, I also only had a Grade 1 acute GVHD and (very) limited chronic GVHD that lasted for 1 month after I discontinued my Prograf. Maybe thist cell therapy sounds "exciting" to some patients since they have to deal with the side effects of never ending cycles of Revlimid, etc. but appears to be a "step back" from the excellent quality of life the upfront allo has provided for me and thousands of other patients.
"Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expand the possible indications for chimeric-antigen receptor (CAR)-T cells. B-cell maturation antigen (BCMA) is expressed only on mature B cells and plasma cells and promotes their survival. BCMA is a promising target for CAR-T cells in multiple myeloma."
http://www.ncbi.nlm.nih.gov/pubmed/23444214
Does this mean a myeloma patient would have no B cells or plasma cells? How would they get enough IVIG to give to a large number of patients since this therapy does not allow them to have healthy functioning immune systems if the therapy "works"?
I am a "hard grader" with respect to therapy since my Immunology Panel is all in the normal range 2.5 years after my allo, I also only had a Grade 1 acute GVHD and (very) limited chronic GVHD that lasted for 1 month after I discontinued my Prograf. Maybe thist cell therapy sounds "exciting" to some patients since they have to deal with the side effects of never ending cycles of Revlimid, etc. but appears to be a "step back" from the excellent quality of life the upfront allo has provided for me and thousands of other patients.
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Mark
Re: Treating collected stem cells to kill myeloma cells
Hi Terry H.,
The success of syngeneic transplants for myeloma is not only due to the patients receiving a clean graft. Some Doctors at Dana Farber did a study on a patient that did a syngeneic transplant and found that the exact match sibling's immune system did help fight the myeloma.
"Targets of curative donor-derived graft-versus-myeloma (GvM) responses following allogeneic hematopoietic stem cell transplantation (HSCT) remain poorly defined, partly because immunity against minor histocompatibility antigens (mHAgs) complicates the elucidation of multiple myeloma (multiple myeloma)-specific targets. We hypothesized that syngeneic HSCT would facilitate the identification of GvM-associated antigens since donor immune responses in this setting should exclusively target unique tumor antigens in the absence of donor-host genetic disparities. We therefore studied the development of tumor immunity in an HLA-A0201+ multiple myeloma patient who achieved durable remission after myeloablative syngeneic HSCT. Using high-density protein microarrays to screen post-HSCT plasma, we identified six antigens that elicited high-titer (1:5,000-1:10,000) antibodies that correlated with clinical tumor regression. Two antigens (DAPK2, PIM1) had enriched expression in primary multiple myeloma tissues. Both elicited antibody responses in other multiple myeloma patients following chemotherapy or HSCT (11 and 6 of 32 patients for DAPK2 and PIM1, respectively). The index patient also developed specific CD8+ T cell responses to HLA-A2 restricted peptides derived from DAPK2 and PIM1. Peptide-specific T cells recognized HLA-A2+ MM-derived cell lines and primary multiple myeloma tumor cells. Coordinated T and B cell immunity develops against MM-associated antigens following syngeneic HSCT. DAPK1 and PIM1 are promising target antigens for MM-directed immunotherapy."
http://bloodjournal.hematologylibrary.org/content/early/2012/01/19/blood-2011-11-388926.full.pdf
A clean graft helps but a healthy functioning donor immune system appears to be the key to the long term remissions myeloma patients can have after syngeneic and allogeneic transplants.
Mark
The success of syngeneic transplants for myeloma is not only due to the patients receiving a clean graft. Some Doctors at Dana Farber did a study on a patient that did a syngeneic transplant and found that the exact match sibling's immune system did help fight the myeloma.
"Targets of curative donor-derived graft-versus-myeloma (GvM) responses following allogeneic hematopoietic stem cell transplantation (HSCT) remain poorly defined, partly because immunity against minor histocompatibility antigens (mHAgs) complicates the elucidation of multiple myeloma (multiple myeloma)-specific targets. We hypothesized that syngeneic HSCT would facilitate the identification of GvM-associated antigens since donor immune responses in this setting should exclusively target unique tumor antigens in the absence of donor-host genetic disparities. We therefore studied the development of tumor immunity in an HLA-A0201+ multiple myeloma patient who achieved durable remission after myeloablative syngeneic HSCT. Using high-density protein microarrays to screen post-HSCT plasma, we identified six antigens that elicited high-titer (1:5,000-1:10,000) antibodies that correlated with clinical tumor regression. Two antigens (DAPK2, PIM1) had enriched expression in primary multiple myeloma tissues. Both elicited antibody responses in other multiple myeloma patients following chemotherapy or HSCT (11 and 6 of 32 patients for DAPK2 and PIM1, respectively). The index patient also developed specific CD8+ T cell responses to HLA-A2 restricted peptides derived from DAPK2 and PIM1. Peptide-specific T cells recognized HLA-A2+ MM-derived cell lines and primary multiple myeloma tumor cells. Coordinated T and B cell immunity develops against MM-associated antigens following syngeneic HSCT. DAPK1 and PIM1 are promising target antigens for MM-directed immunotherapy."
http://bloodjournal.hematologylibrary.org/content/early/2012/01/19/blood-2011-11-388926.full.pdf
A clean graft helps but a healthy functioning donor immune system appears to be the key to the long term remissions myeloma patients can have after syngeneic and allogeneic transplants.
Mark
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Mark
Re: Treating collected stem cells to kill myeloma cells
Dear Mark,
Your point is well taken. The success of Dr. June's approach relies on the ability to find a protein antigen on the surface of the cancer cell that is preferably not expressed at all on normal tissues or, as a next best option, on a highly limited number of cell types and tissues. Thus, a CAR-based approach utilizing BCMA as the target would be expected to deplete someone of at least a subset of normal mature B cells and plasma cells. This could lead to hypogammaglobulinemia (just like the CLL and ALL patients who received CAR-based therapy using CD19 as the target antigen), requiring monthy IVIG.
These approaches will take time, extensive research and revision, just as the allogeneic stem cell transplant process has over decades. However, as we better understand how cancers evade the immune system, it seems that therapies that "re-awaken" the immune system or reprogram them would be worthy of further investigation and could eventually replace the approach where we replace one's entire immune system with that of a donor's.
Pete V.
Your point is well taken. The success of Dr. June's approach relies on the ability to find a protein antigen on the surface of the cancer cell that is preferably not expressed at all on normal tissues or, as a next best option, on a highly limited number of cell types and tissues. Thus, a CAR-based approach utilizing BCMA as the target would be expected to deplete someone of at least a subset of normal mature B cells and plasma cells. This could lead to hypogammaglobulinemia (just like the CLL and ALL patients who received CAR-based therapy using CD19 as the target antigen), requiring monthy IVIG.
These approaches will take time, extensive research and revision, just as the allogeneic stem cell transplant process has over decades. However, as we better understand how cancers evade the immune system, it seems that therapies that "re-awaken" the immune system or reprogram them would be worthy of further investigation and could eventually replace the approach where we replace one's entire immune system with that of a donor's.
Pete V.
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Dr. Peter Voorhees - Name: Peter Voorhees, M.D.
Beacon Medical Advisor
10 posts
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