Do T cells catch a break?

[CaptRon1976]

In following the breathtaking science put forth by Aussie Neil almost daily, I am wondering if CLL weakens or exhausts our precious T cells: do T cells recover or become less exhausted during treatment, be it with BTKI, Ven or combinations? Or do T cells get largely obliterated by treatment?

Ron

[lankisterguy Volunteer]

Hi CaptRon1976,

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This subject usually comes up when CLL Experts are discussing CAR-T and BTKi (like Ibrutinib, Calquence etc.)

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In CAR-T the % success rate for CLL patients is much less than for other NHLs and blood cancers, and the current theories attribute that to "Exhausted" T cells. There are currently several teams exploring ways to overcome that exhaustion. The BTKi seem to help with that and some clinical trials have combined CAR-T and Ibrutinib.

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Here are some articles

thelancet.com/journals/ebio...

ncbi.nlm.nih.gov/pmc/articl....

frontiersin.org/articles/10....

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Len

[CaptRon1976 in reply to lankisterguy]

Thanks Len, I am taking Acal for 9 months with good success so far. With the importance of T cells in mind, I have been wondering since the disease is known to exhaust T cells, how much is known as to whether treatment further diminished T cell capability by eliminating them along with clones and many remaining healthy B cells. Thanks for the references.

Ron

[CaptRon1976 in reply to CaptRon1976]

To put as simply as possible: if T cells become exhausted coping with disease of CLL does treating CLL and greatly decreasing clone numbers thereby “lighten” T cell burden and thereby reduce the T cell exhaustion?

Too simplistic?

[Big_Dee in reply to CaptRon1976]

Hello CaptRon1976

Not too simplistic, I know I get exhausted working with CLL.

[lankisterguy Volunteer in reply to CaptRon1976]

Hi CaptRon1976,

I wish I knew clear and specific answers to your question, but I haven't seen any.

You may want to read this: cancercenter.com/what-are-b...

mdanderson.org/cancerwise/t...

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I don't know that the current targeted therapies or immuno therapies are suspected of eliminating T-cells.

The older Chemo treatments like FCR are used to deplete T-cells in CAR-T treatment just before the modified cells are reinjected into the patient.

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Len

[AussieNeil Partner Administrator in reply to lankisterguy]

BTKi treatments don't affect T cell numbers and while BCL-2i treatments (venetoclax) can reduce some T cell types, in practice it doesn't cause much of a change in T cell counts. I can vouch for that personally, from immunophenotype flow cytometry testing done roughly every 3 months as part of my partition in the AstraZeneca acalabrutinib + venetoclax + obinutuzumab arm of the clinical trial I'm enrolled in. Anti-CD20 monoclonal antibody treatments might also slightly reduce some T cell counts, but again, the effect doesn't seem to affect counts much, if at all.

Good question about whether the T cell exhaustion eventually lifts after treatment. gardening-girl may have some information on that.

Neil

[spi3 in reply to AussieNeil]

Neil, I hope your treatment is successful!

[CaptRon1976 in reply to lankisterguy]

thanks again Len. Two great articles.

[bennevisplace]

According to several research teams, long-term Ibrutinib treatment for CLL reverses T cells' exhaustion and restores their function, e.g.

These findings reveal that long-term ibrutinib therapy is associated with substantial reversal of T cell exhaustion in B-CLL and is likely to contribute to the reduced infection risk seen in association with this agent. ncbi.nlm.nih.gov/pmc/articl...

Whether the same is true of Acalabrutinib one might suspect, but the evidence is less convincing, from what I can see. There's quite a bit of discussion under Table 1 of this review frontiersin.org/articles/10... which concludes with:

Overall, the mechanisms of action for these two drugs [Ibrutinib and Acalabrutinib] on CAR-T cells are not clearly elucidated and represent an interesting area for future investigation. Despite of that, available evidence supports the therapeutic potential of combination or sequential therapies using ibrutinib or acalabrutinib and CAR-T cells.

[CaptRon1976 in reply to bennevisplace]

thanks!

One hopes that the same might prove to be true for the better tolerated BTKI's.

[Jm954 Administrator]

The CLL cells recruit T cells in the microenvironment to enable their proliferation. This non stop stimulation is what exhausts the T cells. BTKi's stop proliferation of CLL cells and T cell function improves.

Here are some posts on CLL and the microenvironment.

healthunlocked.com/cllsuppo...

[CaptRon1976 in reply to Jm954]

thanks Jackie, (sp)

It makes sense the T cells would get to rest a little with treatment. Thanks for the science speaking to it!

Ron

[Gary53]

Before treatment for CLL, chemo 20 years ago I had continuous colds. The T cells were crowded out as were all except useless B cells. For the last 20 years I've not had a viral infection, but a few bad bacterial infections. Now on a drip of blood proteins every 4 weeks to stop that. Ibrutinib tablets every day to clear away the damaged B cells. Hope this non-technical note helps.

[CaptRon1976 in reply to Gary53]

thanks Gary. What are you getting every four weeks to help with bacterial infex, IVIG I am guessing.

[spi3]

Great question! Thank you for asking it.

[skipro]

My docs and studies show CLL has a negative impact on T cell function. Certain CLL treatments do the same.

I had FCR and due to prolonged neutropenia was on Bactrim, Acyclovir, Levoquin and Fluconizole.

After many months my doc checked T cell CD 4, 8, 19, and NK numbers and based on those, stopped the Levo and fluconizole.

2 years later she told me she had no idea what those numbers meant, especially when questioned about the data showing T-cell exhaustion if infected with Covid, which is one of the reasons CLL patients don't do well with the infection and can take months to clear the virus.

The PA for my new doc said T-cells aren't affected, but all the literature I've seen say they are.

After Covid vaccination my various T cell counts all increased dramatically even though I had no antibodies. My immunologist ran a T-cell antigen and mitogen proliferation test to "guestimate" what might happen with Covid. It looked at things like Clostridia Tetanus, Candida A., something called "Con A and B". My numbers were all about 5% of what was expected so he said I had poor T-cell function.

I tried to find labs that test T cells specifically against Covid, but other than a lab in Europe that could Test only CD 4, the only other tests had to be in clinical trial. CD 4 doesn't help much anyway because it tells our non-functioning B- cells to make anti-bodies.

CD8 can kill things directly.

NK or surveillance cells can kill pre-cancers and other things. I've had 8 aggressive skin cancers since doing FCR in 2018. One grew extremely fast just above my right eye during FCR and had suboptimal margins. I've had 2 more grow up near it, one in the right lateral canthus that fortunately had not invaded bone or eye, but required full thickness SG from ear.

I've also had a melanoma, which my doc siad had nothing to do with CLL or treatment although a few papers I've found say otherwise.

One theory I've read is that the skin cancers are due to lack of T-cell function but that its inconclusive evidence.

So that's what I know about T-cells.

Mike Green, ortho surgeon AKA skipro

PS I see a discussion on T cells and BTKi's but have not actual studies to review on the topic. although, some of the AE's listed in some sources about BTKi's list risk of skin cancers. Not sure if it's the CLL itself or the BTKi's.

[CaptRon1976 in reply to skipro]

thanks Mike. Your skepticism is well reasoned IMO.

I have had nine skin cancer surgeries in the last year. Two left wounds large enough to require plastic closures. Three required placental collagen grafts.

As an aging freckle faced redhead one presumes these had origens 60+ years ago. Most appeared pretreatment and likely have some kind of connection to weakened T cells. Hopefully btki tx will help them toughen up a little.

Ron

[skipro in reply to CaptRon1976]

wow

That’s a lot of skin cancer

I too am red headed freclke face kid who did not know about sun screen so much and didn’t use til mid 40’s

Maybe that is as big a risk as CLL

I do hope you are right about BTKi Tx and T cells!!!

God bless

Skipro

[CaptRon1976 in reply to skipro]

yeah, me too.

If Davids and Woyach say so, who am I to argue. Have you had your face to face at Huntsman yet?

[skipro in reply to CaptRon1976]

I’ve been waiting for this for a long time and it had been scheduled 6 weeks ago for this Monday so I’m chomping at the bits. If we chose V + O I can start Teusday. My knee surgery, dental infection and removal of 2 nee cSCC cancers were all just treated last week in n a whirl wind. Good to have good friends in healthcare to expedite.

I was able to get a second opinion set up for 3/23

I’m leaning heavily to BTKi and just want some to start the 2 week prior Auth process

I’m even tempted to just pay $8k out of pocket for the first a 2 week supply to just get started.

Thx

Skipro

[CaptRon1976]

understand. I am interested what your Huntsman doc recommends ALL THINGS CONSIDERED.

I get Acal through Dana Farber specialty pharmacy. My first month in a given year is $3,000. Followed by $800 each month thereafter until the next January. They tell me that after I reach a total lifetime outlay of around $14,000 that Pfizer has a program to supply the drugs at no co-pay cost and just accept the insurance. I haven’t tested that option yet.

Interested in your face to face Monday.

Good luck in deciding.

Ron