Long-Term Ibrutinib Therapy Reverses CD8+ T Ce... - CLL Support

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Long-Term Ibrutinib Therapy Reverses CD8+ T Cell Exhaustion in B Cell CLL

gardening-girl profile image

Chronic Lymphocytic Leukaemia (CLL) is associated with immune suppression and susceptibility to infection. CD8+ T cell numbers are increased and demonstrate elevated expression of PD-1 and impaired function. The mechanisms driving these features of exhaustion are uncertain but are likely to include chronic immune recognition of tumor and/or infectious agents. We investigated the number, phenotype and function of total and virus-specific CD8+ T cells in 65 patients with CLL and 14 patients undergoing long-term ibrutinib therapy (median 21 months). Ibrutinib substantially reduced the number of both CD3+ T cells and CD8+ T cells. Importantly, this was associated with a reduction in PD-1 expression on CD8+ T cells (median 28 vs. 24%; p = 0.042) and 3.5 fold increase in cytokine production following mitogen stimulation. The influence of ibrutinib on antigen-specific CD8+ T cell function was assessed by HLA-peptide tetramers and revealed increased IFNγ and TNFα cytokine responses following stimulation with CMV or EBV peptides together with a 55% reduction in the frequency of “inflated” virus-specific CD8+ T cells. 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. (My bolding)

Front. Immunol., 12 December 2019 doi.org/10.3389/fimmu.2019....

A highly technical, but encouraging, publication.

gardening-girl

18 Replies
lankisterguy profile image
lankisterguyVolunteer

That is great information Gardening Girl - Thanks

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there is some early research suggesting that CAR-T has not been as successful in CLL as in other NHLs and Leukemias due to exhausted T-Cells.

cancer.gov/news-events/canc...

jhoonline.biomedcentral.com...

nature.com/articles/s41586-...

genengnews.com/news/antican...

frontiersin.org/articles/10...

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Len

Len, look what I just found after reading the Nature paper that you referenced above.

Antitumor Potency of an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, Lisocabtagene Maraleucel in Combination With Ibrutinib or Acalabrutinib.

Improvements in expansion and functionality observed in the long-term assays also suggest a potential treatment paradigm for patients undergoing anti-CD19 CAR T-cell therapy. Dosing with BTK inhibitor before CAR T-cell engraftment could serve to reduce tumor size and/or normalize immune functions and microenvironment conditions. Concurrent dosing with BTK inhibitor after administration of CD19-targeted CAR therapies, such as liso-cel, may mitigate any potential in vivo CAR T-cell dysfunction, delay potential exhaustion, or improve CAR T-cell expansion, particularly for CAR T-cell compositions engineered from cells with inferior intrinsic performance. It is important to note that ibrutinib monotherapy is not a curative approach for patients with CLL. As a treatment for relapsed/refractory CLL or for patients with DLBCL with incomplete responses to standard-of-care therapy, an autologous T-cell therapy with a defined ratio of CD4+ and CD8+ T cells engineered to express a second-generation, CD19-directed 4-1BB CAR could be combined with BTK inhibition to provide deeper responses, improve the duration of responses, and target BTK inhibitor–resistant clones before the emergence of progressive disease.

J Immunother. 2020 Jan 2.

journals.lww.com/immunother...

gardening-girl

This is good stuff, thank you for sharing!

Jm954 profile image
Jm954Administrator

This has been mooted for a while and has been the subject of some discussion between my consultant and me, so I was surprised and happy to see he is one of the authors of this paper.

Interesting too to see that the Ibrutinib group had received only up to 32 months of treatment so those of us approaching 5 years of treatment may be doing even better than the group in the paper.

I often give blood for additional research projects and I'm pleased to have possibly been one of the patients reported here.

Thanks for sharing

Jackie

For those still trying to understand how T-cells function and what "checkpoint inhibitors" are, here is an excellent article about 2018 Nobel-winning scientist Jim Allison and his landmark discoveries about the role of T-cells in our immune system. Great reading! (It is also is done using language we can all understand.)

Meet the Carousing, Harmonica-Playing Texan Who Won a Nobel for his Cancer Breakthrough

wired.com/story/meet-jim-al...

The promise of immunotherapy is obvious. We just need a new generation of Jim Allisons doing the science for the ultimate cures. Never Give Up & Be Well - cujoe

cujoe profile image
cujoe in reply to cujoe

And from MedPageToday an update on immunotheraphy via TedTalk by Carl June, MD, director of the Center for Cellular Immunotherapies at Penn Medicine in Philadelphia. He speaks specifically about his successes treating CLL patients with CAR-T. Unfortunately, the cost of this is way out of reach for non-1%ers except via trials.

medpagetoday.com/tedmed/ted...

The description of the high-fever symptoms of patients who respond to CAR-T sound very similar to those of the William Coley who purposely infected cancer patients with bacteria to cause an immune response characterized by very high fevers. High fevers = chicken or egg of curative benefits. Food for thought - Be Well - cujoe

I’m under the understanding that ibrutinibs off target kinase inhibition is responsible for this action. This probably won’t be seen with Acalabrutinib.

avzuclav profile image
avzuclav in reply to Justasheet1

I'm not sure if this is the same phenomenon, but it seems to be an opposite conclusion.

Ibrutinib, but not acalabrutinib, inhibits anti-lymphoma T cell and NK cell function

"In conclusion, ibrutinib, but not acalabrutinib inhibits the activation and function of anti-tumor T and NK cells in vivo and in vitro. "

jimmunol.org/content/202/1_...

avzuclav, I just read the abstract to which you provided the link above. Unfortunately is is presented only as a Supplement to the journal and therefore was probably presented as a poster with no way to access the materials, methods and data. I checked the web site of the senior author, Joshua Brody, and this publication is not listed as a publication, nor were there any other publications related to this one, nor could I find any citations of it. It does seem to contradict other reports.

There have been several references over the past 3 or so years reporting the positive effects of ibrutinib on T cell functioning.

Here are a couple of them:

Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia

Blood. 2016 Mar 3; 127(9): 1117–1127.

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

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Ibrutinib treatment improves T cell number and function in CLL patients.

J Clin Invest. 2017 Aug 1;127(8):3052-3064. doi: 10.1172/JCI89756.

ncbi.nlm.nih.gov/pubmed/287...

Jeff, the authors make a point of pointing out that some of the off-target effects of ibrutinib will be missing from acalabrutinib-treated T-cells, but in spite of that, show that both are indeed effective in enhancing the potential of CAR T-cell therapy by an as-yet-to-be-explained mechanism.

To quote from the paper:

"The present study has been conducted to differentiate direct effects on the intrinsic biology of CAR T cells from pleiotropic effects on the tumor environment that act primarily in vivo. In addition, by comparing acalabrutinib, a highly selective agent, with ibrutinib, the relative contribution of ibrutinib off-target kinase activities, in particular, ITK inhibition, can be evaluated in CAR T-cell functional development.

Our results demonstrate that both ibrutinib and acalabrutinib positively influence CAR T cells in vitro and in vivo antitumor functionalities following long-term treatment. These results indicate the potential suitability of combination therapy using either a BTK inhibitor agent with CAR T-cell therapies.

In vivo efficacy and pharmacokinetic phenotyping of the anti-CD19 CAR T cells isolated from the bone marrow reinforced the observation that both BTK inhibitors may improve CAR T-cell functionality and facilitate a memory-like phenotype.

Because acalabrutinib has limited ITK activity and did not affect CAR T-cell Th1 skewing based on surface markers or significantly altered gene expression, yet still provides benefit to the CAR T cells tested here, it is not clear mechanistically how BTK inhibitors improve functionality.

"

It's sort of amazing that 21 months is the median, I've been on ibrutinib for 84 months. I'm not sure how improved my response rate is to infection if it wasn't for the IVIG I get monthly. I missed the infusion one month and immediately had septic pneumonia.

Livinglifewell, please keep in mind that the IVIG infusions that you receive can only be fully effective if you have functional T cells. 😊

AussieNeil profile image
AussieNeilAdministrator in reply to gardening-girl

Functional helper T cells are essential in the process by which immunoglobulins specific to a new infection are made, but I'm not aware of any further role of T cells with IgG or other immunoglobulins for that matter. Could you explain/provide a reference?

In the "Key Points" section of "Antibody Functions" in Boundless Biology courses.lumenlearning.com/b...

Antibodies/Immunoglobulins "can act independently against extracellular pathogen and toxins.

Antibodies bind to specific antigens on pathogens; this binding can inhibit pathogen infectivity by blocking key extracellular sites, such as receptors involved in host cell entry.

Antibodies can also induce the innate immune response to destroy a pathogen, by activating phagocytes such as macrophages or neutrophils, which are attracted to antibody-bound cells."

Thanks for the very encouraging reference on immune system recovery of T cells with long term Ibrutinib and probably other BTKi use, such as Acalabrutinib.

Neil

Neil, In my answer to Livinglifewell, I only meant that it takes both IgG and effective T cells to stay healthy. One does not replace or substitute for the other except perhaps for the role of Helper T (CD4+) cells in antibody production. T cell involvement in B cell production of immunoglobulins is only one of many T cell functions. Other roles in fighting infection involve Cytotoxic T cells (CD8+ T cells), Regulatory T cells (suppressor T cells), Natural Killer T (NKT) cells and Memory T cells

thoughtco.com/t-cells-meani...

or en.wikipedia.org/wiki/T_cell

Thanks for the link above to "Antibody Functions" in Boundless Biology. It is a wonderful introduction to antibodies!

AussieNeil profile image
AussieNeilAdministrator in reply to gardening-girl

Thanks for your clarifying reply. One of the challenges of living with CLL is indeed the wide range of ways in which CLL cripples our immune system. I misinterpreted your phrase "IVIG infusions that you receive can only be fully effective if you have functional T cells" to imply that there was a dependency on T cells for IGIV to be fully effective. Perhaps "fully reconstituted" is what you meant, though other Ig factors are only partially compensated by IgG.

Neil

Generally very encouraging news. But unfortunately, Ibrutinib is not “the wonder drug” for everyone. If I had to choose between IVIG and Ibrutinib, I would choose IVIG. When I don’t get my infusion on time I get sick almost immediately.

I wish I could hear what Dr. Jain was saying about "Serial T cell and NK cell Numbers" in this presentation yesterday: twitter.com/doctorpemm/stat...

Wow! I have just seen your post, 10 months late. Please keep posting, I'm following you.

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