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I caught up with Dr. David Maloney of the Fred Hutch and Seattle Cancer Care Alliance when we were both in Amsterdam for the annual congress of the European Hematology Association (EHA).
Among other job titles, Dr. Maloney is Medical Director, Cellular Immunotherapy, Immunotherapy Integrated Research Center at the Hutch, and was one of my doctors during my CAR-T trial March- May of 2018.
What those titles tells us is that he has been working for decades on developing an immune therapy that uses our body’s own cells, namely modified T lymphocytes or CAR-T cells.
I was a beneficiary of those years and years of work by Dr. Maloney and Dr. June and so many other researching pioneers, and of course all the brave patients who were in the early trials.
- CAR-T is a living drug a cellular and immune therapy.
- The patient’s own genetically modified T cells are serial killers that expand in vivo (in the body), kill their target cells and then move on to kill more.
- CD19 is the target most commonly used in CLL as that marker is found on nearly all CLL cancer cells, but also on nearly all stages of B cells.
- That is also helpful because a simple test (flow cytometry) can determine if there are any B cells left in the blood or marrow, and if they are none, that means that there must be persistent functional CAR-T cells still playing Whack-A-Mole with any emerging cancer cells and with normal B cells too. Checking for CAR-T cells directly is tougher and is only done at research facilities.
- The speed at which the modified T cells grow when reinfused into the patient is one factor that determines toxicity. If there are too many cells infused or if they expand too fast, the CRS (Cytokine Release Syndrome) from all the inflammation associated with rapid killing can be severe and even life threatening.
- The CAR-T that I received (JCAR-14) uses the 4-1BB co-stimulatory domain to make the T cell active. Other CAR-T constructs use CD28 that is more potent and leads to more rapid expansion but perhaps also quicker exhaustion. See this for details on this topic.
- It seems that both the amount of the expansion of the CAR-T cells and their persistence are important to the durability of the remission. How high or how long are still unknowns.
- The mix of CD4 and CD8 cells may also be important. JCAR-14 and JCAR-17 both have 1:1 ratio of these two CAR-T populations. Other CAR-T products care less about this ratio.
- Ibrutinib improves response rate to CAR-T because
- It makes “better” T cells. In CLL, T cells are often dysfunctional and ibrutinib can turn that around.
- There is less CRS, but not less neurological events
- These benefits are independent of ibrutinib’s effect on the CLL itself and work even those whose CLL is resistant to ibrutinib.
- After CAR-T, achieving U-MRD (Undetectable Minimal Residual Disease) by NGS (next generation sequencing) that can find as few as 1 in 1,000,000 cancer cells is associated with a low risk of relapse.
- While getting to U-MRD6 is associated with more durable responses, it still may not be deep enough to cure our chronic lymphocytic leukemia. There still may be billions of CLL cells left hidden below the level our detection. They may never reappear, or it may take years to reach a level of clinical significance.
- Still, as I have said for years, you can’t get to CURE without passing U-MRD on the way.
Both Dr. Maloney and I believe that CAR-T has a big role to play in CLL and other blood cancer. I bet my life on it, but it is very early in the development process. CAR-T will keep getting better and better.
For a deeper dive, please enjoy this accessible but more detailed interview with Dr. Maloney.
Thanks for reading and watching.
We are all in this together.