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Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46 Page 17

months [75,181,182] . This well-tolerated profile is associated with a reduction in T cells and a simultaneous
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+
[183]
increase of CD8 T and NK cells . In patients with metastatic uveal melanoma, these changes in immune
cell composition were associated with longer-than-expected overall survival (median OS of 20.8 compared
[110]
to historic OS of 7.8 months) . Whether roginolisib has the potential to overcome resistance to
immunotherapy or prevent disease hyperprogression will be the objective of future investigation.
“Molecular glue” compounds, which are derived from cyclosporin A and FK506, are an emerging class of
agents for clinical investigation . Targeting IKZF2 (the gene that encodes for the zinc finger protein
[184]
HELIOS, a member of the Ikaros family of transcription factors), the novel glue degrader NVP-DKY709
(=DKY709) reduces tumor resident and circulating T cells . Because HELIOS is uniquely expressed in a
[185]
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subset of T cells , this approach promises a selective depletion of T cells. DKY709 has been under
[39]
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clinical investigation in a Phase 1 study since 2019, either as a monotherapy or in combination with the PD1
inhibitors PDR001 (NCT03891953; accessed 3rd December 2023). Results on the biomarker responses are
soon to be presented.
Reprogramming of T cells provides an additional approach to reduce or alter the function of
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T cells [186-188] . One such agent is the MALT1 inhibitor, MPT-0118, which in murine models showed a
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change in tumor-resident T cells while not affecting T cells in healthy tissue . This approach can
[189]
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reduce the anticipated toxicity associated with global T cell inhibition. In the first-in-human dose clinical
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trial, a low toxicity rate was observed along with some functional re-programming of T cells .
[190]
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Lastly, there are a growing number of approved small molecules that seem to affect T cells, although they
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were not specifically designed to target T cell pathways. We will highlight a few examples to illustrate such
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underappreciated drugs and their potential as immunotherapeutics. CDK4/6 inhibitors can reduce T cells
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and improve immune responses in patients with breast cancer . Similarly, breast cancer patients treated
[155]
with trastuzumab, either alone or in combination with chemotherapy, showed a reduction in T cells .
[191]
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The JAK1/2 inhibitor ruxolitinib is associated with a reduction in T cells in patients with primary
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myelofibrosis [130,131] . The FLT3 inhibitor midostaurin reduced T cells in PBMCs from patients with
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[193]
AML . Whether this effect is mediated via Dendritic Cells is being investigated . The BCL2 inhibitor
[192]
venetoclax, alone and in combination with pembrolizumab, improves immune responses and is associated
with the reduction in T cells in animal studies . SRC inhibition represents another target for T cell
[156]
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modification. The SRC inhibitor dasatinib seems to reduce T cells and enhance immune responses in
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preclinical models . While these aforementioned approved small molecule inhibitors do not specifically
[194]
target signaling pathways in T cells, they seem to have clinical benefits associated with a reduction in
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T cells. This opens a new avenue for the rapid development of new immunotherapies with established
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agents as pursued by clinical research initiatives [195,196] .
CONCLUSION
Lessons from the drug development of CTLA-4 inhibitors may provide valuable insights to successfully
develop new therapies targeting T cells. The research on T cells has uncovered a T cell population with
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great plasticity. Despite their relatively small size, T cells play a critical role in modulating immune
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responses to tumors. Hence, for novel drugs to be successfully developed in the clinic, the appropriate
methods to assess the function of T cells need to be evaluated alongside the standard measures of clinical
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benefit. The discovery of the precise pharmacologic platform (i.e., large or small molecule) that will deliver
the greatest advantage is currently an exciting area of drug development.