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Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46 Page 13

determine whether a change is clinically meaningful.

In hematologic malignancies, T cells play a role in the regulation of bone marrow progenitor cells, in
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controlling the development of malignant clones (e.g., either by transcriptional changes in the malignant B-
or T cell), and in influencing the immune cell composition. Some examples are used to illustrate the
complexity of targeting T cells in hematologic malignancies. Patients with chronic lymphocytic leukemia
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[125]
(CLL) and responding to PI3K inhibitors idelalisib or duvelisib show a reduction in T cells .
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Interestingly, this reduction in T cells seemed to coincide with toxicities reminiscent of autoimmune
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[126]
toxicities observed in patients receiving ICI . Therefore, treatments with oral PI3K-δ inhibitors have
offered new insights into the role of T cells or their mediators, such as the underappreciated role of IL-
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17 [127-129] . Whether this effect of PI3K-δ inhibitors is uniquely related to the reduction in T cells remains to
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be determined, because a reduction or inhibition of the function of T cells is not always associated with
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autoimmune toxicities. One example of T cell reduction without autoimmune toxicities is observed in
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patients receiving Janus kinase (JAK) 1/2 inhibitors in Primary Myelofibrosis (PMF). Patients who respond
to the treatment with the JAK 1/2 inhibitor ruxolitinib show a decrease in T cells . Interestingly, the
[130]
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highest frequency of T cells was observed in patients with the highest allele frequency of the JAK2 V617F
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mutation. Furthermore, long-term treatment with ruxolitinib was associated with disease control and
[131]
reduction in T cells . In contrast to the experience with CTLA-4 targeting agents and PI3K inhibitors,
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the reduction in T cells was not associated with autoimmune toxicities. There are at least two factors that
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may explain the autoimmune toxicities in patients treated with anti-CTLA-4 antibodies or PI3K-δ
inhibitors, while they are absent in patients receiving agents while reducing T cells. First, common among
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both drug groups is the question about specificity and selectivity. For example, monoclonal antibodies with
a modified Fc framework have an altered response and perhaps also a reduced autoimmune-toxicity
profile [132,133] . Additionally, for the designated PI3K-δ inhibitors, such as idelalisib , parsaclisib and
[135]
[134]
[136]
duvelisib , the selectivity profile in humans is less clear. All known PI3K-δ inhibitors are not as selective as
originally assumed with some important safety implications as recently evaluated . Second, in addition to
[137]
specificity or high selectivity, the immune competency of patients may play a role. For example, in patients
with CLL, the B cell function is disrupted. Hence, it is possible that the reduction in T cells induces the
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elevation of cytotoxic Th17 T cells .
[125]
Examples of drugs targeting T cells and T cell-mediated resistance [Table 4]
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The success of the CTLA-4 targeting agents such as ipilimumab has provided important lessons for future
drug development concepts. Herein, we review drug candidates with specific inhibition profiles for T cells.
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Furthermore, the novel agents intend to provide a greater benefit/risk profile. Drugs designed to increase
the T cells, such as for improving transplantation outcomes, will not be reviewed.
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The lessons from the drug development of such agents support the hypothesis that T cells are key players
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in the resistance mechanisms of immunotherapy . This explains the increasing number of drug candidates
[157]
targeting T cells with an aim to rebalance the overall immune cell compartment [12,158] .
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Large Molecules: Because of the preferential expression of CTLA-4 on T cells, CTLA-4 inhibitors, such as
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ipilimumab or tremelimumab, are perhaps the prototype of selective T cell inhibitors, although a
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reduction in T cells cannot always be detected [138-140,159] . Both ipilimumab and tremelimumab have received
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[160]
approvals for a wide range of indications and form the backbone of many standard treatments . With a
greater understanding of dose and dose schedule, the use of CTLA-4 targeting agents is evolving. For
example, it appears that continuous dosing may not be required to achieve the full effect of CTLA-4
targeting agents [104,161,162] . This is best observed in the neo-adjuvant setting, where limited doses of