[Tracy J]

CAR T-cell therapy & other immunotherapy

by Tracy J on Fri Oct 16, 2015 10:36 am

I had a second opinion from Dr. Adam Cohen at the University of Pennsylvania last week. We talked about an hour.

1. I learned some interesting things about CAR T-cell therapy. The research is proceeding apace. They have targets lined up like airplanes on a runway, just waiting to be tested. They are soon opening a new trial, using BCMA as the target. Identifier NCT02546167. I don't have any new data for you, but I can tell you that he seemed very matter-of-fact, while at the same time hopeful about all this new research.

An interesting tidbit I learned is that a patient CANNOT have CAR T-cell therapy after an allogeneic transplant. This is because in CAR T-cell therapy, the patient's T cells are removed and manipulated in the lab. Among other things, they are "activated". Then they are put back into the patient. Well, after an allo transplant, those T cells are the DONOR'S T cells. "Activat­ing" them in the lab will lead to horrible graft vs host disease once they are put back into the patient. So much time and energy is spent trying to keep the T cells calm and cool after an allo transplant to reduce graft vs host disease. CAR T-cell therapy is just stirring the pot, and getting the T cells all riled up!

But you CAN have an allogeneic transplant after CAR T-cell therapy.

2. I also learned more about antibody drug conjugate treatments, such as trial NCT02064387, which is testing drug BCMA – GSK28579160. This trial uses the same target as the trial above - BCMA. This is where an antibody is physically linked, at the molecular level, to a powerful chemotherapy drug. The chemotherapy drug stays inactive until the antibody finds its target. Once the antibody finds its target (the myeloma cell), the chemo drug is released and becomes active, killing the myeloma cell. The beauty of this is that the chemo drug leaves healthy cells alone because the antibody doesn't target them. Very potent, toxic chemo agents can be used, with very few side effects and little toxicity, since it leaves healthy cells alone. This technique has been used in other cancers, and there is a breast cancer drug approved for treatment, being used clinically right now.

These are very promising areas of research, but only time will tell if they actually pan out.

[Multibilly]

Re: CAR T-cell therapy & other immunotherapy

by Multibilly on Fri Oct 16, 2015 10:57 am

Hi Tracy,

Thanks for the update.

Interesting that they are using BCMA as a target. Dr. Berenson has been big on BCMA as a simple and cost-effective prognostic marker for awhile now. I believe he tests most of his patient's BCMA levels as a matter of course.

https://ash.confex.com/ash/2014/webprogram/Paper75306.html

[Mark11]

Re: CAR T-cell therapy & other immunotherapy

by Mark11 on Fri Oct 16, 2015 12:25 pm

Hi Tracy J.,

Thanks for the post. I do think BCMA is likely a better target for myeloma as opposed to CD19. Hopefully they will have success with the new trial. The NIH already has one going but I have never seen any data on it.

"An interesting tidbit I learned is that a patient CANNOT have CAR T-cell therapy after an allogeneic transplant. This is because in CAR T-cell therapy, the patient's T cells are removed and manipulated in the lab. Among other things, they are "activated". Then they are put back into the patient. Well, after an allo transplant, those T cells are the DONOR'S T cells. "Activat­ing" them in the lab will lead to horrible graft vs host disease once they are put back into the patient. So much time and energy is spent trying to keep the T cells calm and cool after an allo transplant to reduce graft vs host disease. Car T therapy is just stirring the pot, and getting the T cells all riled up!"

Everything I have read tells me that is not the case. Here is a study discussing CTL019 for ALL that comes right out of UPENN.

"The first reports of efficacy in ALL, although hopeful, needed to be expanded to determine the CR rate. With larger studies now published by 3 groups, using different CD19 CAR designs, the efficacy is even better than expected, with CR rates of 70% to 90%.25⇓-27 Our group has reported a 90% CR rate in 30 pediatric and adult patients with relapsed/refractory ALL treated in Children’s Hospital of Philadelphia (CHOP) and University of Pennsylvania (Penn) phase 1 trials.26 Davila et al reported an 88% CR rate in a cohort of 16 adults with relapsed B-cell ALL treated at Memorial Sloan-Kettering Cancer Center (MSKCC).25 Finally, Lee et al recently reported a 70% CR rate in a National Cancer Institute (NCI) intent-to-treat analysis of 20 children and young adults with ALL.27 All 3 studies included patients with a prior history of allogeneic SCT, and no GVHD was seen.

http://www.bloodjournal.org/content/125/26/4017

Using T-cell therapies is often discussed In papers, particularly after T-cell depleted allo transplants.


"Allogeneic hematopoietic cell transplants adequately depleted of T-cells can reduce or prevent acute and chronic GVHD in both HLA-matched and haplotype-disparate hosts, without post-transplant prophylaxis with immunosuppressive drugs. Recent trials indicate that high doses of CD34+ progenitors from G-CSF mobilized peripheral blood leukocytes isolated and T-cell depleted by immunoadsorption to paramagnetic beads, when administered after myeloablative conditioning with TBI and chemotherapy or chemotherapy alone can secure consistent engraftment and abrogate GVHD in patients with acute leukemia without incurring an increased risk of a recurrent leukemia. Early clinical trials also indicate that high doses of in vitro generated leukemia-reactive donor T-cells can be adoptively transferred and can induce remissions of leukemia relapse without GVHD. Similarly, virus-specific T-cells generated from the transplant donor or an HLA partially matched third party, have induced remissions of Rituxan-refractory EBV lymphomas and can clear CMV disease or viremia persisting despite antiviral therapy in a high proportion of cases. Analyses of treatment responses and failures illustrate both the advantages and limitations of donor or banked, third party-derived T-cells, but underscore the potential of adoptive T-cell therapy in the absence of ongoing immunosuppression."

http://www.ncbi.nlm.nih.gov/pubmed/?term=koehne+allogeneic+platform

Best of luck getting into an immunotherapy trial!

Mark

[Tracy J]

Re: CAR T-cell therapy & other immunotherapy

by Tracy J on Fri Oct 16, 2015 1:01 pm

Mark11,

I remembered something about these publications when I was sitting there with Dr. Cohen, so maybe that's why what he said stood out in my mind. I'm very confused now, and I'll do some research to see if I can figure out what he meant and why he said that.

Tracy

[Edna]

Re: CAR T-cell therapy & other immunotherapy

by Edna on Fri Oct 16, 2015 1:08 pm

Hi Tracy

As you note anti-body drug conjugates have been around for decades to treat some cancers. I worked in an oncology research setting decades ago which was working on such conjugates, especially using monoclonal antibodies.

With the advent of transplants in myeloma treatment the pursuit of this avenue of research, to identify suitable myeloma specific cell markers, has come later than might have been the case for those who could not have transplants and would have benefited from the antibody specificity and reduced drug toxicity of the conjugate approach.

Perhaps that is why I am more cynical about the way research moves when there is excessive competition with narrowly focused thinking in research institutions, rather than cooperative looking at how what other research being undertaken might throw up as the line of enquiry.

Too many people doing similar studies without speaking to each other ( I know this from experience). So in myeloma we have huge differences in opinion- not helpful if one is a patient.

[JPC]

Re: CAR T-cell therapy & other immunotherapy

by JPC on Fri Oct 16, 2015 4:54 pm

Tracy J:

Thank you very much for the very interesting news. Best Regards, JPC