[doctoring]

There's a couple of reasons for why a person may relapse after CAR-T therapy, and much is still under investigation.

One large category is that the attack on the CD19 target has selected for B-cells which have a mutated CD19 or do not express CD19. This part kind of makes sense, and is somewhat understandable.

The other category is roughly that the CAR-T cells fucked up, and this is where things are a little murky. Sometimes the CAR-T cells kind of disappeared really quickly after infusion. Sometimes they're there but there's no significant immune response. Remember the therapy uses the patient's own T-cells which get "armed" outside the body and then re-infused. What if the patient's own T-cells are kind of uh, wimpy? Or their immune system overall is? (We know, for example, that T-cell immunity in general declines over age, which probably partly explains better results in younger patients than older).

Anyways, for various reasons, you can see why just "doing it again" may not work due to some issue with the targeting and the immune reaction.

Oh and also CAR-T therapy is not benign. You can get intense cytokine release syndrome where the (intended) activation of your immune system causes a ton of systemic effects (sometimes resulting in organ failure, seizures, death).

Nevertheless, sometimes they do try it again. I've had patients they've attempted CAR-T two or three times on. As you may guess, it was not effective.

[omarhaneef]

It seems it would be effective if the B-cells were still emitting CD-21 or some other target.

I thought that they manage the CRS pretty well these days. Is it still a major risk?

I would be very curious to know more about this wimpy or no response. I am doubly surprised that it doesn't help to just do more.

[doctoring]

Choosing another target is a good idea! But, as you can imagine, we've been trying a lot of targets and they don't seem to work as well. One issue is that CD19 is the only known target that is a) expressed throughout the entirety of the B-cell lifespan, b) fairly preserved under immunological pressure, and c) is not expressed on other cells. Other targets do not maintain those characteristics and as such either won't catch all the tumor cells or will catch too many other cells. (CD21, for example, is also expressed on T-cells.)

That being said, there are studies ongoing for some of these targets in like "last last resort" capacity, as well as certain dual-target CAR-Ts looking at CD19 + another (CD22 or CD123, for example), to try to widen the net while tolerating a degree of on-target but non-tumor effects.

One could also imagine a way to more rapidly alter a patient's CAR-Ts such that you could quickly switch targets, or update them if their malignant CD19 was mutating. Currently the manufacture and production of CAR-T cells is very slow and expensive process, but I do have some friends working on improving that. Some are also working on the idea of a sort of "blank slate" CAR-T cell line which could be used in anybody, rather than being harvested from the particular patient in question.

re: CRS. It is still a significant risk, but our understanding has definitely dramatically improved over the past 10 years. We're getting better and better at anticipating, appropriately triaging, and providing necessary diagnostics & supportive care. That being said, severe outcomes and death do still occur. I don't know the numbers, to be honest.

re: the wimpy response. I am less well-versed in the immunological complexities but there are just so many steps which could contribute. Part of the CAR-T cell success requires them to continue to clonally expand after infusion into the body, and sometimes after infusion they just... don't. Or only a tiny subpopulation of them does. Why? We're not sure. Sometimes they fail to recruit the body's immune response. Why? Also not sure. Maybe it has to do with the health of the T-cells when they were harvested? Maybe something went wrong with the CAR engineering? Maybe with the host immune system?

Here's a decent overview of some mechanisms of relapse after CAR-T which might be a good jumping off point: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863137/

[omarhaneef]

Great article. thank you.

It seems following up with CD22 is a useful practice:

"Another Single-Targeted CAR T-Cell Loss of CD19 is a common mechanism of relapse after treatment with CD19-targeted CAR T-cells. Similar to CD19, CD22 is also diffusely expressed in B cells in patients with B-ALL (92–96), and CD22 expression can be detected in a number of patients with CD19-negative relapses (14). Single-targeted CD22 CAR T-cell therapy is also a common therapeutic tactic for CD19-negative relapse. A phase I dose-escalation trial of a novel CD22-CAR with a 4-1BB domain was conducted (97), which enrolled 21 children and adults with R/R B-ALL, involving 17 children who did not receive CD19-directed immunotherapy. A CR rate of 73% was observed in patients receiving CD22-CAR T-cells, involving 5 patients with dim or without expression of CD19 in leukemia cells."

Although I am confused because the next section, while touting the benefits of CD19/CD22 cocktail doesn't present much better statistics:

"Sequential Infusion of Two Groups of Single-Targeted CAR T-Cells Clinical studies (98) have shown that sequential infusion of third-generation CD19 and CD22 CAR T-cells, which is called cocktail therapy, is feasible and safe for patients with R/R B-ALL (Figure 4A). In a clinical trial, cocktail therapy was used to treat 27 patients with R/R B-ALL. As a consequence, the trial yielded a 6-month OS rate of 79% and an event-free survival rate of 72% with sustained remission, in which 24/27 (88.9%) patients received CR or CRi, and 13/27 (48.1%) patients attained MRD-negative CR. The center subsequently enrolled more candidates (99), among whom 81 patients received CAR22 T-cells following the infusion of CD19 CARs, while 8 patients received CD19 CARs following the infusion of CD22 CARs. The median follow-up time was 7.6 months. Among 50 evaluable patients, 48 (96.0%) achieved CR/CRi by day 30, 94% of whom were MRD-negative. The PFS of B-ALL patients was 12.0 months, and the median OS was not reached. In total, 23 patients experienced a relapse, with no CD19 or CD22 antigen loss observed. Drawing on the finding that a high MRD-negative rate in R/R ALL patients was achieved by sequential infusion of third-generation CD22 and CD19 CAR T-cells, demonstrating this method has great feasibility for the treatment of CD19-negative relapse ALL."

[spopejoy]

It's at least better than most chemos. If CAR-T introduced a decent remission (1-3 years) and didn't invoke CRS, you can at least consider trying it again, unlike doxyrubicin etc.

[panabee]

thanks for all the wonderful explanations.

are you on researchgate or twitter?

it would be great to follow you since you seem current on the latest research.