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Researchers have been actively exploring the potential of introducing highly potent cancer-specific T cells
into solid tumors as an innovative strategy. Encouraging findings have been observed, particularly with
fourth-generation anti-CD133 CAR T-cells, which have demonstrated significant effectiveness against BTC
[109]
cells expressing CD133 . Additionally, the combination of CAR T therapies targeting both EGFR and
CD133 in a cocktail immunotherapy approach has produced promising outcomes in advanced BTC
[110]
patients . Furthermore, a phase I study (NCT01869166) involving EGFR-specific CAR T cells for EGFR-
mutated advanced BTC has shown favorable results, including a 5.8% CR rate and stable disease in 58.8% of
[111]
patients .
Moreover, at the 2023 ASCO meeting, results from a phase I trial using gavocabtagene autoleucel, an
autologous genetically engineered anti-mesothelin T cell receptor fusion construct cell therapy, were
presented . This trial focused on patients with refractory mesothelioma and other mesothelin-expressing
[112]
solid tumors, including BTC. The results were promising, with an ORR of 21% and a DCR of 77% among
the 32 patients who participated in the study, including one patient with BTC. Furthermore, the 6-month
OS rate reached 70.2%. These findings suggest a potential avenue for effective treatment in patients with
mesothelioma patients and other mesothelin-expressing solid tumors, offering hope in the fight against
these challenging malignancies. Nevertheless, concerns about the toxicity of CAR T-cell therapy in BTC
persist, mainly due to potential toxicity and endothelial damage, emphasizing the imperative for further
investigation and the conduct of clinical trials.

In conclusion, while CAR T-cell therapy has significantly advanced the treatment of hematologic
malignancies, its application for solid tumors, including BTC, brings forth a landscape filled with both
promise and hurdles. Research involving CAR T cells targeting specific antigens such as CD133 and EGFR
has demonstrated effectiveness in both preclinical and clinical contexts, instilling hope for patients with
conditions like BTC. Nonetheless, persisting safety concerns and the imperative for more extensive research
underscore the continuous endeavors to enhance the potential of CAR T-cell therapies for solid tumors,
with the ultimate goal of improving their efficacy while mitigating potential adverse effects.

CHALLENGES AND POTENTIALS OF TARGETED THERAPIES
Sequencing of cancer genomics
The evolution of targeted therapy is closely intertwined with the advancements in DNA sequencing
technology used in cancer cells. Cancer, being a genomic disease, is often influenced by both somatic and
germline mutations, highlighting the crucial need to comprehend cancer's genomic sequencing in order to
uncover its origins and develop personalized treatment approaches. Recent progress and cost reductions in
NGS have greatly accelerated the transformation of cancer genomic data into practical clinical applications.
It allows simultaneous analysis of hundreds or thousands of genes, empowering the implementation of
molecularly targeted therapy based on the insights gained from the results.

NGS technology has enabled the identification of genomic profiles for individual cancer cells, paving the
way for personalized treatment approaches. However, the diversity of tumor genomic sub-categories
identified by NGS makes it exceedingly difficult to conduct randomized controlled trials with an adequate
number of patients for each specific sub-category . Furthermore, the intratumoral environment consists
[113]
of diverse and heterogeneous cells, resulting in variations in genomic profiles and mutation data among
these cells. As a consequence, there are concerns about the feasibility of relying solely on sequencing results
[114]
to determine the most suitable targeted therapy .