ESMO Asia 2025 | Novel immunotherapies and cell therapies in hepatobiliary cancers

For patients with hepatobiliary cancers, there are novel modalities and emerging targets. Among the emerging therapeutic modalities, we have next-generation immune checkpoint inhibitors, antibody drug conjugates, ADCs, cell therapies, and multimodal therapies, so combination of immunotherapy with local regional therapies. But regarding the three first new modalities, so next-generation ICIs, ADCs, and cell therapies, there are some interesting data. For the new immune checkpoint inhibitors, one of the most important targets is TIGIT. And different phase two and three studies with TIGIT as a target have been conducted in GI cancers. And these trials have non-homogeneous results. So some are positive, some negative, some still ongoing. The drugs they use, the antibodies they use are different. What is interesting is that there is a bispecific antibody that is called relvegostomy that targets PD-1 antigen. Being a bispecific antibody, it targets both the antigens. And the dual blockade of PD-1 and TIGIT could increase antitumor immunity. And this was shown in preclinical and clinical studies, even if in other cancer types. But what is important is that the bispecific format can improve the targeting of both TIGIT and PD-1 anti-cells and promote a superior and increased activity compared to co-administration of individual components. So it’s better to use, it’s probably better because it’s still to be demonstrated, but it’s probably better to use a bispecific antibody compared to the two different antibodies. And relvegostomy has been evaluated in several global phase three trials across GI cancers, in biliary tract cancers, in the adjuvant setting in combination with chemotherapy, and in the advanced setting in first line in HER2-positive tumors in combination with chemotherapy and trastuzumab-deruxtecan. In gastric cancer, again, in first line in HER2-positive tumors in combination with chemotherapy and trastuzumab-deruxtecan. In gastric cancer, again, in first line, in HER2-positive tumors, in combination with chemotherapy, relvegostomy, and trastuzumab-deruxtecan. And in hepatocellular carcinoma, in HCC, in first line, in combination with bevacizumab plus or minus atezolizumab. So different cancer types, different settings, different combinations for relvegostomy. Then there are the ADCs. The mechanism of action of the ADCs is well known. They have a potent target-specific anti-cancer killing effect and the therapeutic index is improved compared to conventional chemotherapy due to the release of the payload inside of the tumor cells. There are multiple types of ADCs, and the differences are based on the targets, the linker, and the payload. ADCs are being tested in different early phase clinical trials, phase 1, first in human, that include HCC, with different targets, MET, GPC3, PD-L1, EGFR. So different targets, different drugs, and different studies. And these are recruiting, these are enrolling patients. For biliary tract cancer, we already have some results for Trastuzumab deruxtecan, from the DESTINY-PAN tumor 02, that is a global phase 2 study that included different cancer types. And for patients with a HER2-positive biliary tract cancer, especially patients with immunohistochemistry 3+, we have very promising results with a median progression-free survival of 7.4 months and an overall response rate of 56%. And this drug now is being tested in first line in combination with immunotherapy, as previously mentioned, in global phase 3 study in first line in patients with HER2 positive biliary tract cancer. Then we have cell therapies. Cell therapies can be autologous cell therapies or allogenic. And for autologous, we have CAR T cells or TCR T cells. CAR T are T cells derived from patients and engineered to express surface proteins that target antigens on the surface of cancer cells. TCR, T cells, again, are patient-derived T cells engineered to recognize a tumor-specific protein fragment with MHC combination within cancer cells. So different mechanisms, but then both of these are two different types of autologous cell therapies. And then we have the allogenic, and these are cell lines derived from primary T cells from a healthy donor, again engineered to express a CAR or a TCR. So different options also for the CAR T cells. And there are preliminary data in HCC with a novel TGF beta receptor to dominant negative ARMOR CAR T that targets a GPC3 to treat patients with advanced unresectable HCC. This is very interesting because GPC3 is highly expressed in HCC, 70%, but has limited expression in normal tissue. And armoring resists the TGF-beta, that is a potent immunosuppressive cytokine, which negatively correlates with prognosis. So TGF-beta armoring is highly relevant to HCC. And with this new CAR-T, there are encouraging efficacy results in HCC with a small number of patients so far, 24 patients, but most of them benefited from the treatment. And also in terms of safety, the safety profile is favorable. CRS, grade three CRS has been observed only in one patient and in one patient I can see no patient. These are typical adverse events of CAR T cells. So it’s very, very promising. So overall, what we can say is that immunotherapy now is immunotherapy combinations are the standard of care for patients with advanced HCC and BTC, so hepatobiliary. But of course, we need to improve the results and we need to broaden the patient population that can be treated with immunotherapy combinations. And there are novel mechanisms of action, new combinations, innovative strategies. I’ve just mentioned cell therapies, bispecific antibodies, ADCs, and emerging targets that are currently being investigated in clinical trials. So to expand the opportunities and in the future to have a more personalized treatment options and hopefully we will be able to improve the prognosis of our patients.

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