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Page 16 Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46

antibody NEO20, which targets CAECAM-5 and -6, reduced T cells only in patients with long-term stable
reg
[147]
disease (SD) . Therefore, the observations from the early clinical trials with the anti-CD38 and anti-
CEACAM-5 monoclonal antibodies suggest that factors other than selectivity are important in the design of
novel T cell inhibitors.
reg

Small Molecules: In addition to the large molecules, small molecules are being used to target signaling
pathways uniquely or preferentially present in T cells. There is an increasing list of small molecules that
reg
have been associated with the regulation of T cells . Perhaps the most common treatments associated
[171]
reg
with a reduction in T cells are chemotherapies, such as cyclophosphamide, either as a therapy alone or in
reg
combination with vaccines . In particular, the low dose cyclophosphamide (50 mg twice a day for a
[148]
[150]
2-week of a 4-week cycle) is associated with a reduction in T cells and an increase in T cells . A
reg
eff
variation of this administration is the metronomic regimen which also generates reproducible changes in
T cells . Other chemotherapies with immunomodulatory effects include regimens containing docetaxel
[149]
reg
in NSCLC [151,172] , sunitinib in renal cell carcinoma , and cisplatin plus vinorelbine in breast and lung
[151]
cancer .
[151]
Chemotherapies are not sufficiently selective for T cells and their subsets. Hence, more specific inhibitors
reg
may target unique pathways of T cells, such as targeting FOXP3. Recently, a screen from different
reg
compounds found potential candidates that would directly degrade FOXP3, such as derivatives of gallic
acid . AZD8701 is an antisense oligonucleotide (ASO) blocking STAT3 and thus indirectly FOXP3 .
[152]
[173]
During the Phase 1 study of AZD8701 in combination with durvalumab (NCT00637039), the FOXP3
expression was reduced with a concurrent reduction in T cells.
reg
Following the drug development experience of large molecules targeting CCR4, small molecule inhibitors of
CCR4 are being investigated in patients . For example, CCR4-351 is a small molecule inhibitor of CCR4,
[174]
which reduces T cells in animal and in vitro models . CCR4 small molecule inhibitors block the
[174]
reg
migration of T cells and therefore keep T cells from entering the tumor microenvironment . Despite a
[175]
reg
reg
wide range of different CCR4 small molecule inhibitors, their clinical development has not led to an
approved agent to this date .
[176]
Another approach is blocking signaling pathways downstream of T cell receptors or co-stimulatory
molecules. One such pathway is the PI3K-δ signaling pathway . By blocking PI3K-δ signaling, T cells
[177]
reg
show reduced proliferation and, in patients’ plasma, chemokines such as CCL2, CCL3, CCL5, and CCL22
are decreased [125,154] . In solid tumors, blocking PI3K-δ signaling modulated immune homeostasis and
reinforced PD-1 blockade . Based on this observation, the combination of pembrolizumab with
[178]
parsaclisib (a designated PI3K-δ inhibitor) was investigated in patients who had progressed on prior
immunotherapies . Unlike the combination of pembrolizumab with the JAK1 inhibitor itacitinib,
[179]
parsaclisib rebalanced the immune environment towards an interferon (IFN)-γ signature. Patients receiving
the combination of parsaclisib and pembrolizumab also showed responses in both ICI-naïve and ICI
therapy-resistant tumors (8/28 patients; 28%). Another designated PI3K-δ inhibitor, AMG-319, was
investigated in patients with head and neck cancers . In post-treatment biopsies, T cells were reduced
[153]
reg
only in patients who tolerated AMG-319 for approximately 2 weeks, and thus were able to complete their
scheduled treatment period. The tumor responses were minor and transient, most likely because the
treatment was relatively short. These adenosine triphosphate (ATP)-competitive and designated PI3K-δ
inhibitors, such as AMG-319 or idelalisib, have limitations due to their toxicity profile in patients with solid
[180]
malignancies . By contrast, the non-ATP, allosteric modulator and highly selective PI3K-δ inhibitor,
roginolisib (IOA-244), has a lower rate of severe toxicity, which allows for treatments lasting greater than 6