[Dan D]

Immune System Indicators of Long-Term Disease Control

by Dan D on Tue Jul 10, 2012 2:23 pm

The following abstract was just published - -and I think it is noteworthy because it begins to describe the gradual changes in the immune system that herald long-term disease control in some patients. And these include patients who revert back to an MGUS type condition.

So perhaps this may offer comfort during maintenance period -- as opposed to just wating for a relapse.

It may also merit the benefits of an integrative approach to maintenance that emphasizes immune system strengthening (such as increasing NK and cytotoxic T cell activity) to take control of the disease in the long run.


Haematologica. 2012 Jul 6. [Epub ahead of print]
Analysis of the immune system of multiple myeloma patients achieving long-term disease control, by multidimensional flow cytometry.
Pessoa-Magalhaes RJ, Vidriales MB, Paiva B, Gimenez CF, Garcia-Sanz R, Mateos MV, Gutierrez N, Lecrevisse Q, Blanco JF, Hernandez J, de Las Heras N, Martinez J, Roig M, da Costa ES, Ocio E, Perez-Andres M, Maiolino A, Nucci M, Delarubia J, Lahuerta JJ, San Miguel JF, Orfao A.
SourceBrasil;

Abstract
Background. Multiple myeloma remains largely incurable. However, a few patients experience ≥10-years relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with complete response, since some revert into an MGUS profile.

Design and Methods. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of long-term disease control multiple myeloma (n=28) vs. both newly-diagnosed MGUS (n=23) and symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10).

Results. Similarly to MGUS and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+T-cells and NK-cells. However, bone marrow Tregs were reduced in long-term disease control vs. symptomatic multiple myeloma. Noteworthy, B-cells were depleted in MGUS and symptomatic multiple myeloma, while recovered in long-term disease control patients in both bone marrow and peripheral blood, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B-cells. The number of bone marrow dendritic cells and tissue macrophages significantly differed between long-term disease control and symptomatic multiple myeloma with a recovery trend in the former patient population towards levels similar to those found in healthy adults.

Conclusions. In summary, our results indicate that long-term disease control multiple myeloma patients have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting an improved immunesurveillance.Keywords: myeloma, long term follow-up, immunesurveillance, T-cells, Tregs, B-cells.

[Nancy Shamanna]

Re: Immune System Indicators of Long-Term Disease Control

by Nancy Shamanna on Tue Jul 10, 2012 4:04 pm

Thanks Dan, That is the sort of good news that is nice to hear! I suppose the question for patients is 'how do we best boost our immune system, so that improvements such as those described in the abstract can best happen?".

[Dan D]

Re: Immune System Indicators of Long-Term Disease Control

by Dan D on Tue Jul 10, 2012 5:08 pm

To begin addressing your questions, I am including a link to a tremendous book that I have been reading and that is probably at your local library.

Life Over Cancer: The Block Center Program for Integrative Cancer Treatment. (Keith Block)

I think it shows the way. It discusses how, following reduction of tumor bulk after chemo, one can take charge of the remission process -- and even remain in remission -- through a combination of approaches, including nutrition, supplements, exercise, hormones, and other modalities.

In other words it is commonsense approach that combines conventional cancer care -- which is a must - with integrative care. That said, the book acknowledges that alternative approaches alone - such as nutrition -- do not offer a cure. You have to knock back the cancer with drugs first, so that you have an adequate foundation for rebuilding your defenses.

As quoted by the Block Center itself, their goal is to "use every potential strategy to strengthen your body with the goal of eradicating the cancer with which you’ve been diagnosed; and, then, we work with you to build your body and its defenses to help you protect against cancer in the future."

[Nancy Shamanna]

Re: Immune System Indicators of Long-Term Disease Control

by Nancy Shamanna on Tue Jul 10, 2012 6:07 pm

Thanks Dan...six copies of that book are available in our public library and I have put it on hold! I already am trying to keep my immune system strong by exercising daily and eating properly, getting enough rest etc. Because fortunately I am not on treatment right now, this is easier to do now than it was during the treatment phase. One's lifestyle choices seem more important than ever when contending with cancer though!!

[Mark]

Re: Immune System Indicators of Long-Term Disease Control

by Mark on Tue Jul 10, 2012 8:57 pm

Dan D

I would look at this study as further evidence as to why younger patients should do allo transplants early in disease course. It is common knowledge that patients that do allos have a better chance of attaining long term disease control since the Donor immune system has a better chance of functioning normally than the patients own immune system since myeloma is cancer of the plasma cells. Plasma cells are part of your immune system. That is the reason so few non-allo patients attain long term disease freedom. All my Doctor talks with me about is getting the Donor immune system "up to speed' so that I do not relapse. That is why I do not do never ending cycles of myeloma therapy. My Doctors goal was to get me off all myeloma therapy ASAP. Don't all myeloma Doctors discuss the immune systems role in their disease with their patients?

Mark

[Dan D]

Re: Immune System Indicators of Long-Term Disease Control

by Dan D on Tue Jul 10, 2012 10:32 pm

Hi Mark

Not sure how much doctors discuss the overall role of the immune system in their disease. I suspect not enough.

As for allos and long-term disease control, I wonder whether the disease control is more a reflection of a manageable graft versus host response rather than a restoration of normal immune system function. And of course, UNmanageable GVH disease is the biggest concern of allo transplants. But it sounds like you hit the sweet spot?

Plasma cells are certainly part of the immune system -- but they are a very differentiated cell type pumping out antibody, far removed from less mature B cells and completely distinct from T cells and NK cells. multiple myeloma is not cancer of immature immune cells - - it is not B-cell or T-cell leukemia -- and yet these immature, otherwise normal cells are the ones that are completelly obliterated by the chemical treatments that precede transplant. Why not work with the good cells I do have?

So I leave with the same comment I began with: I am not sure. You may be right. But I certainly am sure that you can aid your own cause during remission.

[Mark]

Re: Immune System Indicators of Long-Term Disease Control

by Mark on Wed Jul 11, 2012 9:58 am

Dan D.,

I agree with you that the immune system is the key to a cure/good outcome in myeloma. I just wanted to point out that there are myeloma Doctors that are very aware of how powerful a properly functioning immune system. Not all extoll the virtues of never ending cycles of drugs like Dr. Berenson, Dr. Barlogie, or Andrzej Jakubowiak do.

As far as a myeloma patient not wanting to destroy their "healthy functioning" immune cells, I do not think that should be much of an issue. Here is how those healthy cells are functioning in myeloma patients:

"2. Immune Abnormalities in multiple myeloma Patients

The number and function of T cells subsets are aberrant in patients with multiple myeloma [5, 6]. The CD4 : CD8 ratio is inverted and the helper T-cell type 1 to type 2 (Th1 : Th2) ratio among CD4 cells is abnormal [7]. In addition, the levels of expression of CD28 costimulatory molecules required for T cell activation are downregulated in T cells derived from multiple myeloma patients [8]. The elevated levels of transforming growth factor (TGF)-β, in addition to the impaired accessory signals from Th cells, contribute to the presence of dysfunctional B cells [9]. Defective natural killer cells (NK) have also been noted in multiple myeloma patients [10]. Circulating dendritic cells (DCs) from multiple myeloma patients were shown to be dysfunctional, failing to upregulate costimulatory molecules required for DCs activation, which led to reduced phagocytic activity and antigen presentation [11]."
http://www.hindawi.com/journals/bmr/2011/269519/

The process by how donor transplants work is quite complex. Dr. Ken Anderson and his collegues at Dana Farber did an interesting experiment. They did a lot of testing on a patient in long term remission that did a syngeneic transplant. A syngeneic transplant is very rare because few patients have an exact twin. Kathy Giusti of the MMRF has been in remission for like 15 years since she recieved her twin sisters healthy immune system. Patients that do syngeneic rarely have GVHD.

"Targets of curative donor-derived graft-versus-myeloma (GVM) responses after allogeneic hematopoietic stem cell transplantation (HSCT) remain poorly defined, partly because immunity against minor histocompatibility Ags (mHAgs) complicates the elucidation of multiple myeloma (multiple myeloma)-specific targets. We hypothesized that syngeneic HSCT would facilitate the identification of GVM-associated Ags because donor immune responses in this setting should exclusively target unique tumor Ags in the absence of donor-host genetic disparities"
"Two Ags (DAPK2 and PIM1) had enriched expression in primary multiple myeloma tissues. Both elicited Ab responses in other multiple myeloma patients after 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 Ags after syngeneic HSCT. DAPK1 and PIM1 are promising target Ags for MM-directed immunotherapy."
http://www.ncbi.nlm.nih.gov/pubmed/22267603

There is quite a bit of information about the immune systems role in patients with myeloma. The more I read about it the more I understand why immunotherapy approaches other than allo transplantation have had little success in myeloma.

Mark

[Dan D]

Re: Immune System Indicators of Long-Term Disease Control

by Dan D on Wed Jul 11, 2012 12:34 pm

Thanks Mark

Very interesting. I wonder if the DAPK2 and PIM1 antigens identifed by the Dana Farber group are part of the vaccine they are developing? That said, I do agree that immunotherapy has not enjoyed much success. But the experiment you described may be a key insight.

[suzierose]

Re: Immune System Indicators of Long-Term Disease Control

by suzierose on Thu Jul 12, 2012 1:01 pm

Hi Dan,

Thanks for the book reference. I think I will head to bookstore to pick up a copy today. I like the concept of integrative cancer care. Evanston, ILL, is not really on the beaten path, though

However, I found this notably as well:

"When chemotherapy is required, doctors at the Block Center use a unique method of drug delivery called chronomodulated chemotherapy, also known as chronotherapy, which seeks to coordinate the body’s biological rhythms with the application of chemotherapy. Every drug has an optimal time of application when it is least toxic and most effective.

The Block Center is the first US medical clinic to use a portable, computerized, FDA-approved pump to administer chronotherapy. Unlike conventionally infused chemotherapy, this chronomodulated method provides a coordinated rhythm of dosing based on “timing.” Infusion of the chemotherapy drug resembles a perfectly symmetrical wave, called a sine wave curve: it starts slowly and ratchets up, hour by hour, slowly increasing to the middle point of the cycle, where it peaks and infuses most of the drug, and then slowly ratchets back down. The timing of the drug is based on several important factors related to the medication’s characteristics, the patient’s circadian rhythms, and the nature of the cancer. This coordination of biological rhythms creates a better “kill rate” for the cancer, with less toxicity to healthy cells. Patients are able to wear this small portable pump in a fanny pack around their waist, allowing them to be active during treatment and maintain routine activities."

I suspect many patients experience less toxicity with this kind of individualized dosing regimen.

Thanks for a great reference!

[Ron Harvot]

Re: Immune System Indicators of Long-Term Disease Control

by Ron Harvot on Sun Jul 15, 2012 7:06 pm

I have been on RVD for 3 1/2 years. This past week I developed viral meningitis and C Diff. I was hospitalized for 4 days and now am on an antibiotic for the C Diff and an anti viral for the meningitis. All of this was due to my immune system being compromised. My oncologist has stopped my chemo until I recover. He is also going to start me on immunological infusions once a month to boost my immune system. Has anyone else experienced anything like this?

Ron