Page 147 - Read Online

Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46 Page 15

In addition to the approved anti-CTLA-4 agents, the group of approved anti-PD-1 targeting agents, such as
pembrolizumab and nivolumab, can reduce T cells. In contrast to CTLA-4, PD1 is not preferentially
reg
expressed on T cells. Therefore, the ratio of PD1 expressing T and T cells can be used as a monitor for
reg
eff
reg
+
response [108,164,165] . Whether the PD1 T cells are functionally immunosuppressive or have reduced
reg
functional activity remains a topic of ongoing research [141,165] . Since both main groups of ICI (i.e., CTLA-4
and PD1 targeting agents) affect T cells, clinical studies evaluating T cells during ICI therapies may
reg
reg
provide valuable information for the development of novel inhibitors of T cells.
reg
The chemokine receptor CCR4 is expressed on T cells. For example, the monoclonal antibody against
reg
CCR4, mogamulizumab, is approved for relapsed or refractory mycosis fungoides (MF) or Sézary syndrome
[142]
(SS) . Although mogamulizumab achieved an ORR of 10% in a diverse population with solid tumors ,
[166]
T cells in tumor tissue and circulating blood were reduced in patients with tumor responses, while there
reg
were no changes or even increases in T cells for patients who progressed.
reg
In addition to the above-mentioned approved monoclonal antibodies, there are several drug development
candidates designed to target specific proteins on T cells. One such drug is GS-1811, a monoclonal
reg
antibody blocking CCR8 on T cells [143,144] . This antibody is designed to remove the highly immune
reg
suppressive T cells, which express CCR8. This approach of reducing a specific subset of T cells may
reg
reg
address the toxicity concerns otherwise observed with the CTLA-4 targeting agents. Furthermore, it appears
that the expression of CCR8 is highly restricted to tumor-infiltrating T cells .
[144]
reg
Targeting CD25 on T cells is another selective approach to block T cells. RO7296682 (also known as
reg
reg
RG6292), a monoclonal antibody designed to specifically block the CD25-mediated function on T cells, is
reg
currently under clinical investigation (NCT04158583) . Due to its design, RO7296682 promises to be
[145]
more selective and less toxic than prior anti-CD25 monoclonal antibodies, such as daclizumab or
basiliximab. As with GS-1811, the anticipated benefit is the reduced toxicity profile compared to the
approved CTLA-4 targeting monoclonal antibodies.
Early non-clinical and clinical development efforts are currently targeting the ligand of CD25. This
approach relies on blocking IL-2 or modifying the binding of IL-2. Recent technologies can generate
multivalent, asymmetric IL-2-Fc fusions with different binding properties (including variable forms to
[167]
either block or activate T cells) . A more traditional approach consists in the generation of specific IL-2
reg
[146]
blocking antibodies, such as AU-007 . AU-007 binds to the CD25-binding epitope of IL-2, which prevents
the interaction with the trimeric IL-2R expressed on T cells, while not affecting the dimer of the IL-2R on
reg
memory or naïve T and NK cells. Patients receiving AU-007 had a decrease in T cells, with an increase in
reg
CD8 T cells. This approach may overcome the known drug resistance in triple-negative breast cancer,
+
[168]
where CD25 T cells are associated with resistance to immunotherapy .
+
reg
The surface protein CD38 is present on a wide range of immune cells, including T cells. The reduction in
reg
T cells following dosing of the anti-CD38 monoclonal antibody isatuximab plus atezolizumab in patients
reg
with advanced solid tumors was evaluated . Surprisingly, isatuximab plus atezolizumab was not associated
[169]
with a reduction in T cells, although nearly all patients showed a reduction in CD38 T cells. The low
+
reg
overall response rate, diverse patient population, and low immune cell population at baseline may explain
the lack of detectable changes in T cells.
reg
The carcinoembryonic antigen-related cell adhesion molecules (CEACAM)-5 and CEACAM-6 are
expressed on tumor cells and T cells with a profound immunosuppressive function . The monoclonal
[170]
reg