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Tumor Discovery EpCAM-targeting cancer immunotherapies

treatment success rates could be improved, and associated clinical practice. This concept may be considered in
off-target toxicity limited, by targeting CSRs that are future therapy development and clinical trial designs,
both overexpressed in cancer cells and under-expressed including patient selection and measurement of baseline
in proximal and distal healthy tissues. In light of this, characteristics. In addition, the development of new
statistical methods, machine learning, and predictive therapies may require an improved understanding of the
modeling have been applied to determine which CSRs in biology and signaling pathways associated with EpCAM
breast cancer subtypes, if targeted by therapeutics, would such that their selective efficacy is dependent on the
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have the lowest likelihood of off-target toxicity. However, affinity of the receptor-targeting domain, which drives
the varied outcomes in pre-/clinical settings when the toxic domains to the target in the case of armed
targeting EpCAM can be attributed to the substantial antibody therapies. Importantly, the high specificity of the
heterogeneity of EpCAM expression, both within tumor EpCAM-targeting ligands can contribute to limiting off-
subtypes and between diseased and healthy tissues target toxicities and interference with signaling pathways
suggesting that EpCAM may not be an “easy’’ therapeutic involving similar surface receptors through crosstalk
target. 42,43 Although monoclonal antibody-based signaling. However, it is important to strike the balance
immunotherapy was the first to undergo clinical testing between the binding affinity of anti-EpCAM ligands and
against EpCAM-positive cancers, an increasing focus on on- and off-target toxicities. In this context, our group and
armed antibody-based targeted therapies, specifically others have demonstrated the potential of recombinant
rIT, has been subjected to clinical evaluation in recent antibodies fused to the N-terminus of bacteria and
decades. This trend may be attributed to the marginal human-based toxins for the generation of rITs and
successes achieved by relying on monoclonal antibodies cytolytic fusion proteins targeting multiple cancers. 54,55
as monotherapy. Researchers have recognized the In addition to these advances, other immunotherapeutics
importance of actively inducing cytotoxicity in EpCAM- such as CAR T, cytokines, therapeutic nucleic acids,
positive tumor cells by arming antibodies with bacterial and oncolytic viruses for the therapy of EpCAM-
or plant-derived toxins. Nevertheless, adverse effects positive cancers are under development, harboring
associated with earlier generations of rITs have primarily the potential to transition into clinical evaluations. 55-58
emerged from dose-limiting antidrug immune responses Furthermore, arming EpCAM-targeting antibodies with
and vascular leak syndromes, which have led to severe humanized toxin moieties is a promising approach for
clinical complications. 47,48 Furthermore, immunotherapy reducing antitoxin immune responses. In this regard,
strategies such as BiTEs, cytokines, ACTs targeting supercomputing and protein engineering techniques
EpCAM overexpression, and recruitment of cytotoxic T aimed at identifying and ablating reactive epitopes while
cells to tumor sites have made significant strides in clinical retaining the cytolytic properties of the attached toxin
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studies, despite some minor limitations. For instance, the remain the gold standard that needs to be explored.
favorable clinical outcomes of anti-EpCAM BiTEs were These approaches, together with the development of
only observed in combination with chemotherapy. This is less immunogenic and humanized toxin domains and
similar to the limited clinical trial reports on ACTs (which the activation of antitumor immune effectors, are the
mainly rely on T-cell mediated cytotoxicity) and therefore desired anti-EpCAM-targeted therapeutic strategies
may require active immunotherapy or chemoradiation awaiting future applications. Finally, high-throughput
combination for improved efficacy against EpCAM- analysis of spatiotemporal distribution, identification,
positive solid cancers. Because clinical endpoints of and capitalization on significant tumor vulnerabilities,
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early-phase clinical testing are measured with the toxicity as well as the density of EpCAM overexpression in
and efficacy profiles, there is a need to strike a balance heterogeneous tumor lesions remain important factors
in designing future EpCAM-specific clinical trials. In to be explored. 60-62 Taken together, these suggestions may
this regard, EpCAM-specific immunotherapy may be guide the design of future clinical trials allowing for the
enhanced by adopting a more recent innovative approach potential approval of EpCAM-specific immunotherapies.
such as the delivery of therapeutic payloads by envelope-
targeted vectors. 50 Acknowledgments

Furthermore, EpCAM overexpression mediates D.M.D. acknowledges the award of the Google PhD
the development of resistance to several anticancer Fellowship by Google LLC.
therapies in different tumor types. 51-53 This induced Funding
tumor plasticity post-therapy observed in pre-clinical
models partly contributes to the challenges affecting This work is based on the research supported by the South
the smooth translation of anti-EpCAM therapies into African Research Chairs Initiative of the Department

Volume 4 Issue 1 (2025) 9 doi: 10.36922/td.4926