Rebooting Immune System at Johns Hopkins

[CVfactor]

It looks like Johns Hopkins is working on another approach to reboot the immune system by using a certain chemotherapy drug that destroys immune system cells with the exception of stem cells (no transplant required).

http://m.hopkinsmedicine.org/news/media ... d_patients

It seems to be similar to what Dr. Burt is doing at Northwestern but does not require stem cell harvesting. It is an early trial with a limited number of patients but from what I have read it is not nearly as expensive as the other approaches. I think it may be something worth investigating for those with no options but believe re-booting your immune system is the answer.

[merlin26]

It looks like Johns Hopkins is working on another approach to reboot the immune system by using a certain chemotherapy drug that destroys immune system cells with the exception of stem cells (no transplant required).

http://m.hopkinsmedicine.org/news/media ... d_patients

It seems to be similar to what Dr. Burt is doing at Northwestern but does not require stem cell harvesting. It is an early trial with a limited number of patients but from what I have read it is not nearly as expensive as the other approaches. I think it may be something worth investigating for those with no options but believe re-booting your immune system is the answer.

Hey CV, that article is from 2008 and that trial has been over and done with for a while now. Chrishasms and others have already gone through the John Hopkins trial with mixed results. There is a hicy forum on this board detailing those individuals experiences with this particular protocol.

[CVfactor]

merlin,
Thanks, I didnt see this category on this forum but it does not look like it is a very active topic.

I noticed they were treating "the worst of the worst" ms patients where as Dr. Burt is limiting his patients to RRMS. I can only speculate this may be a cause for the mixed results from the Hi-Cy protocol.

[merlin26]

merlin,
Thanks, I didnt see this category on this forum but it does not look like it is a very active topic.

I noticed they were treating "the worst of the worst" ms patients where as Dr. Burt is limiting his patients to RRMS. I can only speculate this may be a cause for the mixed results from the Hi-Cy protocol.

Hey CV, actually they were treating both RRMS and some progressives as well. I looked up the forum links for you if you'd like to check them out? I myself almost went through the JH trial 4 years ago. Here are the links:

http://www.thisisms.com/forum/revimmune ... c5905.html

http://www.thisisms.com/forum/general-d ... ic693.html

http://www.thisisms.com/forum/revimmune ... c5423.html

[CVfactor]

Thanks for the info merlin. I think it would be important to know if people who were RRMS did better than those that are progressives using Hi-Cy. This would be of interest since it seems that the trials for HSCT in the US are limiting participation to only relapsing MS types.

[georgegoss]

The Hopkins researchers patented the use of high-dose cyclophosphamide (Cytoxan, Revimmune) in the US for theraputic use of Multiple Sclerosis, and other hematologically-rooted autoimmune diseases. They have recently sold the patent and associated rights to Accentia Biopharmaceuticals, Inc which the company has now renamed 'Cyrevia.' Accentia has planned (but not yet started) a randomized phase III clinical trial of Cyrevia and unfortunately is not yet approved by the FDA. Also, because of the reliquishment of the rights, Johns Hopkins can no longer offer the treatment. When finally released, I think this will be an excellent drug (better than all the other CRAB drugs) and am really happy to see it come to market. However, because Cyrevia is a single chemical agent, it is not as effective as the multi-agent chemical therapy used in HSCT because Cyrevia is not as effective in targetting the spreading epitope of self-intolerant autoimmune lymphocytes. The closest comparison of efficacy for the two treatment approaches shown to date is that Cyrevia is effective to stop the underlying MS disease activity and progression in approximately 70% of early RRMS patients, as opposed to essentially 100% of early RRMS patients that are HSCT-treated. I would just hate to be caught in the 30% population in which Cyrevia was ineffective. For me, this makes HSCT a no-brainer since there is no tratment anywhere that can hold a candle to the efficacy to HSCT.

Accentia Biopharmaceuticals Conducts Investigator Meeting in Preparation for New Multiple Sclerosis Drug Study for Cyrevia™

http://finance.yahoo.com/news/accentia- ... 00594.html

And a video showing the clinical development. . . . .

[CVfactor]

No doubt George, but before HSCT becomes approved for MS treatment I would be willing to take a gamble with Hi-Cy to hopefully stop from transitioning to secondary progressive. Especially if it is affordable. It seems the FDA has already approved this for two other autoimmune diseases. Im going to keep my eye on this.

[georgegoss]

No doubt George, but before HSCT becomes approved for MS treatment I would be willing to take a gamble with Hi-Cy to hopefully stop from transitioning to secondary progressive. Especially if it is affordable. It seems the FDA has already approved this for two other autoimmune diseases. Im going to keep my eye on this.

Agreed this looks like it's going to be a great drug. Again, I'm happy to see it come to market.

"But". . . . (isn't there always a caveat?). . . . this "Cyrevia" drug is straight-up cyclophosphamide; an alkylating mustard agent. And just like all alkylating chemical agents (also used in HSCT), there exisits the potential for mutagenesis (causing cancer) that escalates with lifetime dose and exposure. So my own personal worry is what if a Cyrevia-treated patient falls into the 30% category in which the drug fails to arrest the underlying disease activity and progression of MS, then what are the curative treatment options following this? The next logical step along the same lines is to go on to HSCT. But because alkylating agents are lifetime dose dependant, then having Cyrevia followed by HSCT greatly increases (a lot!) the risk that a treated-individual will later develop a secondary cancerous malignancy (usually MDS or AML) that has some serious risk of death.

So as a general rule it is good to limit lifetime exposure of Alkylating agent exposure and having a double-treatetment with alkylating agents is something I would want to avoid. So if I can have superior confidence of a successfull treatment of HSCT to arrest my underlying disease, then I would go for it (HSCT) with one treatment to substantially reduce the chance of both a "failed treatment" and "increased risk of latent cancerous fatality."

Just some food-for-thought. Each individual should make their own decision regarding risk vs reward of any treatment. I would never suppose to make such a decision for anyone else.

[CVfactor]

Thanks George,
As usual you have investigated all options with much detail. I think the best hope in my view is HSCT prior to becoming progressive, but it will be a while before it is accepted treatment availabe to all.

Edit:
After thinking about what you wrote about these agents, it seems it might be of a concern for people who undergo the non-myeoblative method and have to be re-treated after a relapse. Any thoughts?

[georgegoss]

Thanks George,
As usual you have investigated all options with much detail. I think the best hope in my view is HSCT prior to becoming progressive, but it will be a while before it is accepted treatment availabe to all.

Edit:
After thinking about what you wrote about these agents, it seems it might be of a concern for people who undergo the non-myeoblative method and have to be re-treated after a relapse. Any thoughts?

CV, you bring up an excellent point, as usual. I am going to apologize in advance for my long response that I wite in case anyone else doesn't know the background.

Over the past few years of seeing and learning more about the non-myeloablative specific HSCT protocol (heavily dependent upon cyclophosphamide + two additional non-alkylating chemical agents) and clinical results, I am really starting to have some concern about that specific non-myeloablative form of HSCT as opposed to the myeloablative HSCT (which is the one I received). My main concern is not about safety, but efficacy. But of course the two are intertwined. I'll explain my thinking. . . . . .

Myeloablative HSCT (the most widely used protocol being a four-drug regimin of BEAM) is extremely effective at eliminating virtually all of the in-vivo lymphocytes of the body. The four chemicals pretty much ablate the entire compliment of autoreactive lymphocytes of all epitope sub-types that are responsible for underlying MS disease activity and progression. In fact, following myeloablative HSCT the human body is rendered antigen naive, causing the body to loose immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens and vaccines.Because of this it also becomes necessary for myeloablative HSCT recipients to be re-vaccinated for diseases starting from the beginning again, just like a newborn child. An excellent surrogate indicator of the superior effectiveness of this treatment for hematologically-rooted autoimmune conditions such as MS. If there is any chance of stopping MS in a given individual, myeloablative protocols will do it with little remaining doubt.

The non-myeloablative HSCT protocol for the treatent of autoimmune diseases was pioneered by Prof. Shimon Slavin (formerly with Stanford and Fred Hutchinson) here in the US in the 1980's as a way to perform a "gentler" and "safer" (but only partial) immune ablation with a reduced risk of mortality. At that time, the fully myeloablative HSCT treatments were showing a high level of risk with a death rate in the 5-10% range. In the 1990's Dr. Richard Burt teamed up with Prof. Slavin and adopted this "reduced intensity conditioning" (RIC) approach and continued on with his own non-myeloablative clinical trials at NWU in Chicago (currently in phase III today). So the non-myeloablative HSCT protocol (as performed by Dr. Burt at NWU in Chicago) does not ablate the entire compliment of in-vivo lymphocytes, but instead "diminishes" them. So some autorective lymphocytes still survive, but with the objective that these autoreactive lymphocytes will be driven to a low enough population level to render the underlying MS pathology inactive.

Here is a graph I created that shows this difference between the two protocols:

http://2.bp.blogspot.com/-3w43aw2GsWA/T ... rofile.jpg

So the original objective of the non-myeloablative HSCT was appropriate and admirable. . . . . a safer treatment of hematologically autoimmune disorders (and MS specifically) that was still efficacious.

However, two things have happened since the inception of the non-myeloablative clinical trials:

1) The fully-myeloablative (BEAM) HSCT treatment at experienced facilities has significantly improved the safety and mortality rates of the treatment (mainly by making the treatment "proactive" instead of "reactive"). BEAM performed at experienced hospital facilities now has a mortality rate somewhere in the sub-1% range (probably somewhere around 0.8%). The non-myeloablative HSCT protocol as administered at NWU in Chicago has a mortality rate in the range of approximately 0.4%. So clearly today these two treatment protocols are not "that" different in safety profiles. Neither one of which can be characterized as wildly risky.

2) Dr. Burt's non-myeloablative HSCT treatment has shown that a substantial portion of initially-treated patients have failed to have their MS pathology arrested. From the most recent phase II clinical trial data, fully 23% of non-myeloablative treated patients suffered a relapse following initial treatment. Dr. Burt's program identifies such failed treatment cases by identification of relapse activity, and then performs a "retreatment" of six months of monthly cyclophosphamide infusions. This is a very inefficient way to reduce the autoreactive lymphocyte population (the ones that still have antigen memory) because both autoreactive and niave cells are mixed together in the body and the population as a whole gets diminished; with lesser effectivity of autoreactive lymphocyte ablation each monthly re-treatment generation.

So going back to your original comment, it seems that falling into the 23% of failed treatment patients is not a good thing because cyclophosphamide re-treatments up the lifetime expose level and risk of a possible latent malignancy.

Two lessons that I can see from all this. . . . . it seems that in order to not fall into the 23% grouping of failed non-myeloablative HSCT treated patient population, then the myeloablative (BEAM) treatment would be a better option. The advantages being better probability of initial treatment success, together with no required re-treatments that up the chance of latent malignancies. Utilizing a stem cell graft is also a good strategy that allows for use of the "minimum necessary" alkylating chemical expose while still acheiving the objective of inactivating MS disease pathology. Once the myeloablative HSCT treatment is done, its done. No amount of additional re-treatment is going to improve the probability of a successfull outcome. Once is all it takes and there is nothing (yet) shown to work better and to me that means a 'realatively' safe treatment (since not a single MS patient has died from this chemical-only HSCT treatment protocol).

Additionally, what if a SPMS or PPMS treated patient fails to have their underlying MS disease activity arrested via non-myeloablative HSCT? How would you know or identify such a patient? Such patients don't have isolated relapses, just further progression. So for my opinion under all circumstances progressive MS patients should favor the myeloablative HSCT to avoid possibly being stuck in such a difficult-to-diagnose situation.

But I also have to acknowledge there are some downsides (I call them trade-offs) to having the myeloablative HSCT:

- Need to be re-vaccinated (not required with non myeloablative)

- Near-certain infertility and probable hormone dysfunction requiring HRT (This is only a partial chance with non-myeloablative protocol)

- Average longer recovery timeframe

- Slightly greater risk of complications (another reason to have any HSCT procdure performed at a good facility)

[chrishasms]

The one reason they use Cyclophosphamide is the biggest risk is bladder cancer and when Mesna is used to coat the bladder it protects well. I was told for the four days of chemo, it's no different if you had a spoonful of it or a two litter bottle. Plus it's out of your system within 48 hours this way. It's actually pretty darn safe. I know one person 3 treatments down and is fine. Still in remission I think too. Hard to find MS people who feel good lol.

[georgegoss]

The one reason they use Cyclophosphamide is the biggest risk is bladder cancer and when Mesna is used to coat the bladder it protects well. I was told for the four days of chemo, it's no different if you had a spoonful of it or a two litter bottle. Plus it's out of your system within 48 hours this way. It's actually pretty darn safe. I know one person 3 treatments down and is fine. Still in remission I think too. Hard to find MS people who feel good lol.

Good highlight, Chris. Thanks for sharing that relevant info. Bladder cancer is indeed the #1 report secondary malignancy with the use of cyclophosphamide, which is why they often administer it together with the adjuvant ifosfamide (the combination named Mesna). Unfortunately this combination does not specifically "prevent" bladder cancer, but instead immediately treats it as it devlops. But the good news is that the ongoing incidence of chronic bladdedr cancer is reduced with it'a use. Mesna is a good ameliorative drug.

Mesna info:

http://en.wikipedia.org/wiki/Mesna

Unfortunately there is no way to reduce the systemic cancers (myelodisplasia and lymphoproliferative) which are the next most common to develop with the use of cyclophosphamide. These other two cancers have a higher incidence of mortality rates and again, are cyclophosphamide dose-dependant.

Cyclophosphamide drug info & warning:

http://www.drugs.com/monograph/cyclophosphamide.html

"Carcinogenesis - Secondary malignancies, most frequently urinary bladder, myeloproliferative, and lymphoproliferative, have occurred with monotherapy, combination therapy, or adjunctive therapy; may not be detected until several years after discontinuance. . . . . Consider possibility of secondary malignancy when weighing possible benefits versus potential risks."

[chrishasms]

My understanding of it is the cancers were much more prevalent in the people who were on the pulse administration though. Was I told wrong?

[georgegoss]

My understanding of it is the cancers were much more prevalent in the people who were on the pulse administration though. Was I told wrong?

I don't know anything about that (pulse vs. non pulse administration secondary malignancy occurence data). I do know that cyclophosphamide was originally developed and used on many thousands of patients primarily for lymphocytic-based malignancies. So the result data is well-developed and well-understood.