[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Mon Jul 20, 2015 7:10 pm

I just saw some articles describing the results of a TCAR trial for myeloma patients. The TCAR cells were give after autologous transplant. Here is the press release from UPENN.

"For the study, patients received an average of 2.4 billion NY-ESO-engineered CD3 T cells two days after an ASCT. The investigational treatment begins by removing patients' T cells via an apheresis process similar to blood donation, then genetically reprogramming them using a cell production process originally developed by Penn’s Clinical Cell and Vaccine Production Facility. After being infused back into patients’ bodies, these newly built cells both multiply and seek out a peptide expressed by the antigens NY-ESO-1 and LAGE-1 found in multiple myeloma cancer cells.

With a median follow up of 21.1 months, 15 of the 20 patients were surviving and 10 remained progression free, the researchers report.

Fourteen people had near complete responses, while two had a very good partial response, two had a partial response, one had stable disease, and one had progressive disease. As of April 2015, with a median follow up of 30.1 months, the media progression free survival was 19.1 months and the median overall survival had increased to 32.1 months.

What’s more, none of the patients experienced macrophage activate syndrome or cytokine release syndrome, an infusion reaction observed in other gene therapy trials characterized by fever, nausea, chills, hypotension or a rash. There were no treatment-related fatalities.

Relapse was associated with a loss of gene-modified T cells, the authors report, which suggests that methods for sustaining long-term persistence of engineered T cells in more patients may improve outcomes."

http://www.uphs.upenn.edu/news/News_Releases/2015/07/june/


Here is the abstract from the paper.

"Despite recent therapeutic advances, multiple myeloma (multiple myeloma) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive multiple myeloma received an average 2.4 × 109 engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1–LAGE-1 TCR–engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma."

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3910.html

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Tue Jul 21, 2015 6:24 am

For those interested, here is a link to the full paper about the TCR trial from the previous post.

http://www.nature.com/articles/nm.3910.epdf?shared_access_token=YGwCbHN5Q0HjcRcGQXzkEdRgN0jAjWel9jnR3ZoTv0PjOBl8-NIU8DhShaL9tHXAV8v8ytIqiB2wQKbx7CL8Jbm1-iHgOit3E7giAiFNplfbGkMjfQHz-kvJH8pZG2hv7QVieX0mnldpqWyT88UfVCi8OK5f5ZyzEpGIK1LIZPY%3D

[Terrij]

Re: CAR T-cell therapy for multiple myeloma

by Terrij on Tue Jul 21, 2015 9:58 am

Thank you, Mark, for posting this info. You are so knowledgeable on different aspects of treatment for myeloma. It helps to be able to understand some of the new info.

Our daughter is going through a tough time right now but the goal point is to do a trial with T-cell infusions. Not sure of all the protocol yet but we have to take one step at a time.

Once again, thank you for sharing your knowledge.

[Perseverance]

Re: CAR T-cell therapy for multiple myeloma

by Perseverance on Wed Jul 22, 2015 1:39 pm

I'd really like to hear what others think of these data in the T-cell receptor therapy trial done by the University of Maryland and University of Pennsylvania. The data show that 80% of patients responded and 50% are still progression free after almost 2 years follow-up, with evidence of persistence of the engineered cells. This was a heavily pre-treated population.

There was a lot of excitement at ASCO regarding daratumumab, elotuzumab, and carfilzomib vs. bortezomib. These data in the TCR trial indicate similar, if not better, clinical benefit. The one caveat is that the trial is Phase 1 and contained a small patient sample. However, this is the most excited I have been about study results in years. Am I off base?

Mark, also feel free to give your take.

[TerryH]

Re: CAR T-cell therapy for multiple myeloma

by TerryH on Wed Jul 22, 2015 5:59 pm

I'm still processing the results of the recent trial that Mark pointed out (thanks for the link, Mark). However, as much as I'm optimistic about these sorts of novel immunotherapeutic approaches, I'm not seeing anything in the results that suggests to me that this treatment is a real game changer..

First of all, I think it's a bit of an exaggeration to call the patients in the recent trial "heavily pretreated." They had a median of three prior lines of therapy. That's not the five or eight prior lines of therapy you often see in what typically is called "heavily pretreated" disease.

Also, this trial didn't just test an infusion of the modified T cells. The trial involved a stem cell transplant (i.e., high-dose melphalan) followed by the infusion of modified T cells.

So, in that regard, it's worth mentioning that two thirds of the patients (by my quick count) never had a stem cell transplant prior to the trial. Given that the trial was conducted in the U.S., that means those two thirds of the patients probably were never treated with melphalan, let alone high-dose melphalan.

And, remember, the "high" response to treatment in this trial is a combined response to both the high-dose melphalan and the modified T cells. You can't separate the two responses because the modified T cell were infused two days after the patients got their stem cells back.

Finally, buried in the article is the fact that median OVERALL survival in the trial looks like it's just under two years. So, with this treatment, if you're a patient whose had three prior lines of therapy, you could expect to live just another two years after this combined stem cell transplant / modified T cell therapy.

Maybe some people think that's impressive. I don't.

Again, I haven't looked at the paper in depth. These are just the key things I noticed after a quick skim.

[Terrij]

Re: CAR T-cell therapy for multiple myeloma

by Terrij on Wed Jul 22, 2015 8:54 pm

The T-cell therapy is a great hope for my daughter. She has been through 6 prior treatments including a stem cell transplant. Last week she had high-dose, 4-day chemo & will probably do another round in August.

Today her doctor told her that the CAR T-cell infusion Phase 1 trial is opening in September at Penn. This is without an auto transplant. We don't know all the details yet, but he thinks this is the best bet for her. As I have mentioned before, we would do this before the very risky, less likely to work for her allo transplant in which her brother is a half match. T-cell therapy is our hope at this point.

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Sun Aug 23, 2015 7:35 am

I just saw this podcast discussing different immune therapy approaches. For those interested in this subject I thought it is a worthwhile podcast to listen to.

http://noveltargets.com/2015/08/episode-5-titans-of-adoptive-cell-therapy/

In my opinion, it is especially interesting to start listening at around 13:20. This part of the discussion is about why CAR T approaches work better for ALL than it does for CLL, even though both of the blood cancers express CD19 on them. That goes right into a discussion about myeloma.

[Mark11]

Re: CAR T-cell therapy for multiple myeloma

by Mark11 on Sun Aug 23, 2015 8:00 am

Good discussion about the TCR trial above. My opinion is that anything that can improve an auto is a positive thing for myeloma patients since it can be beneficial for a lot of patients. The combination of high dose chemotherapy followed up by immunotherapy (allogeneic transplant) is the one established curative therapy for younger myeloma patients.

Terry H brought up some good points and it also appears that some patients used Revlimid maintenance as well. The patient that had the best response (just short of 3 years with no maintenance) was featured in some news stories. He mentions the good quality of life he had during that time period after his auto. That is rare for a relapsed patient to enjoy a drug free remission period after relapse. I know from personal experience how great quality of life can be during an extended drug free remission following high dose chemo/immunotherapy. That is definitely a positive of the therapy. I also think this patient deserves a lot of credit. If I am reading this correctly he did an auto as a relapsed patient at 73 years old. This is a patient that is definitely willing to do what it takes to have a good outcome.

http://www.baltimoresun.com/health/bs-hs-myeloma-treatment-20150807-story.html

http://www.wbaltv.com/health/doctors-using-patients-immune-system-to-battle-multiple-myeloma/34529218

[ping]

Re: CAR T-cell therapy for multiple myeloma

by ping on Wed Sep 09, 2015 12:38 am

Regarding the study in Nature Medicine that Mark11 mentioned above and TerryH commented on ... As Terry pointed out, the patients in the study also underwent a stem cell transplant as part of the study. Does anyone know if this is necessary? Can this be done without doing an autologous SCT but only removing the blood cells and having them treated in this way?

Thanks for any comments.

Ping

[JPC]

Re: CAR T-cell therapy for multiple myeloma

by JPC on Wed Sep 09, 2015 6:26 am

Hi Ping:

Short answer. Right now, only ASCT trials are available. At some point down the road, when they have figured it out a little better, other settings will be getting trials without the ASCT. It will be interesting to see how quickly they will be able to advance this. Regards,