Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition

Our plain-English summary of Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition, by M. Zhao, L. Li, C.H. Kiernan, et al (Scientific Reports, 2023).

The study

• Authors: M. Zhao, L. Li, C.H. Kiernan, M.D. Castro Eiro, F. Dammeijer, M. van Meurs, I. Brouwers-Haspels, M.E.P. Wilmsen, D.G.B. Grashof, H.J.G. van de Werken, R.W. Hendriks, J.G. Aerts, Y.M. Mueller, P.D. Katsikis
• Journal: Scientific Reports
• Published: 2023;13(1):15678
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cytotoxic CD8 + T cell (CTL) exhaustion is driven by chronic antigen stimulation. Reversing CTL exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. We, therefore, investigated whether modulating chronic antigen stimulation and T-cell receptor (TCR) signaling with an IL2-inducible T-cell kinase (ITK) inhibitor, could confer ICB responsiveness to ICB resistant solid tumors. In vivo intermittent treatment of 3 ICB-resistant solid tumor (melanoma, mesothelioma or pancreatic cancer) with ITK inhibitor significantly improved ICB therapy. ITK inhibition directly reinvigorate exhausted CTL in vitro as it enhanced cytokine production, decreased inhibitory receptor expression, and downregulated the transcription factor TOX. Our study demonstrates that intermittent ITK inhibition can be used to directly ameliorate CTL exhaustion and enhance immunotherapies even in solid tumors that are ICB resistant.

© 2023. Springer Nature Limited.

In plain English

This was a laboratory study in mice and in cultured mouse T cells, testing whether an ITK inhibitor (BMS-509744) could make tumours respond to immune checkpoint blockade. C57BL/6 mice were given one of three tumours under the skin: B16-F10-OVA melanoma, AE17 mesothelioma, or 4662 pancreatic tumour cells. Once tumours were established, mice received the ITK inhibitor at 5 mg/kg intraperitoneally in three-day cycles (three days on, three days off, repeated three times), with or without anti-PD-1 antibody. In the melanoma model, survival on day 35 was 0% with isotype control, 15.4% with ITK inhibitor alone, 38.5% with anti-PD-1 alone and 72.7% with the combination. In the AE17 mesothelioma model, survival on day 46 was 36.4%, 22.2%, 25% and 90% respectively; in the pancreatic model on day 29 it was 5.9%, 0%, 22.2% and 52.9%. In cultured exhausted OT-I CD8 T cells, the inhibitor lowered inhibitory receptors and TOX and increased IL-2 and TNF-alpha producing cells. The authors concluded intermittent ITK inhibition mitigates T cell exhaustion and augments checkpoint blockade.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal (mouse) tumour experiments combined with in vitro experiments on cultured CD8 T cells
• Who was studied: C57BL/6 mice bearing B16-F10-OVA melanoma (n = 9-15), AE17 mesothelioma (n = 12) or 4662 pancreatic tumours (n = 17-18), plus purified OT-I CD8+ T cells exhausted in vitro; Erasmus Medical Center animal facility, Rotterdam
• Exposure: The selective ITK inhibitor BMS-509744, given intermittently in vivo at 5 mg/kg per day (3 days on, 3 days off, three cycles over 18 days), alone or with anti-PD-1 antibody (100 micrograms per mouse, twice weekly); in vitro 1 micromolar BMS-509744 for 3 days
• Main results:
  • B16-F10-OVA melanoma, end of experiment: 0% survival with isotype control and 15.4% with ITK inhibitor alone
  • B16-F10-OVA melanoma, survival on day 35: 38.5% with anti-PD-1 alone and 72.7% with ITK inhibitor plus anti-PD-1
  • AE17 mesothelioma, survival on day 46: 36.4% isotype control, 22.2% ITK inhibitor alone, 25% anti-PD-1 alone
  • AE17 mesothelioma, ITK inhibitor plus anti-PD-1: survival increased to 90%
  • 4662 pancreatic tumour, survival by day 29: 5.9% with isotype control and 0% with ITK inhibitor alone
  • 4662 pancreatic tumour: 22.2% survival with anti-PD-1 alone and 52.9% with ITK inhibitor plus anti-PD-1
  • ITK inhibitor given alone had no therapeutic effect on the solid tumours in vivo, per the authors
  • In vitro exhausted CD8 T cells treated with the ITK inhibitor showed reduced surface expression of the inhibitory receptors PD-1, Lag3, Tigit and Tim3
  • Cytokine production by exhausted cells improved, with more IL-2 and TNF-alpha producing cells, though the authors state the improvement was only partial compared with single peptide stimulated cells
  • ITK inhibition lowered the transcription factor TOX in exhausted cells while TCF1 was unchanged
  • In exhausted T cells, BMS-509744 reduced phosphorylation of ITK (Tyr180) and of its downstream target PLC-gamma1 (Tyr783)
• The authors' conclusion: The authors concluded that intermittent ITK inhibition dampens TCR signalling, mitigates T cell exhaustion and augments checkpoint blockade therapy in ICB-resistant cancers, providing a rationale for testing ITK inhibitors with ICB in patients
• Limitations the authors state:
  • The drug concentration and treatment schedule used in vivo were not optimised, and further studies are needed
  • The pharmacokinetics of the inhibitor used were unknown
  • The method used for tumour growth curves underestimates tumour volumes for animals killed before the end of the experiment
  • Some mice in the ITK inhibitor alone groups did not complete the treatment schedule because they reached the humane endpoint

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Cytokine.

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