What Are the Challenges in Clinical Translation of Targeting TGF-β?

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What Are the Challenges in Clinical Translation of Targeting TGF-β?

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What Are the Challenges in Clinical Translation of Targeting TGF-β?

Transforming growth factor-beta (TGF-β) is an effective multifunctional cytokine that plays complex and often conflicting roles in tumor development. In early-stage tumors, the TGF-β pathway induces apoptosis and inhibits tumor cell proliferation.

Conversely, in advanced stages, it promotes tumor progression through mechanisms such as genomic instability, epithelial-mesenchymal transition (EMT), angiogenesis, immune evasion, cell motility, and metastasis. Currently, TGF-β targeting agents have become a hot topic in research.

Numerous preclinical studies suggest that blocking TGF-β signaling is an effective approach to treating tumors.

It can alleviate Treg-mediated immune suppression, enhance T-cell cytotoxicity, promote T-cell infiltration into the tumor center, leading to a robust anti-tumor immune response and tumor regression. Furthermore, TGF-β blockade enhances the tumor’s response to immune checkpoint inhibitors (ICIs).

However, unlike preclinical results, progress in TGF-β blockade in clinical trials has been challenging, with most trials failing to replicate the success seen in animal models.

Therefore, it is essential to review key clinical trials of TGF-β and PD-1/PD-L1 signal inhibition in solid tumors, analyze the potential reasons for the lack of success in clinical translation, and explore potential strategies to improve response rates in subsequent trials.

Clinical Studies of TGF-β in Combination with ICIs

Colorectal Cancer (CRC)

Combining TGF-β and PD-1/PD-L1 signal inhibition has shown promising anti-tumor activity in preclinical mouse models of colorectal cancer. Several clinical studies are currently underway in CRC patients.

An open-label phase 2 study (NCT03724851) is evaluating the combination of Vactosrtib and Pembrolizumab in previously treated microsatellite-stable (MSS) CRC patients. In the interim analysis, 15.2% (5/33) of patients showed partial responses, and 21.2% (7/33) had stable disease. The combination therapy was well-tolerated, with only three severe adverse events, including pneumonia (3%), nausea (3%), and vomiting (3%). Moderate side effects were more common, including elevated serum amylase (21.2%), itching (21.2%), rash (21.2%), and elevated serum lipase (18.2%).

A dual-function anti-PD-L1/TGF-β fusion protein, Bintrafusp alfa, is also undergoing clinical research in CRC (NCT03436563). A recent phase 2 study in patients with heavily pretreated microsatellite instability-high (MSI-H) metastatic solid tumors, including 12 CRC patients, reported early results. Among 14 evaluable patients, 3 (21.4%) had stable disease, with only one patient achieving long-term clinical benefit. The remaining 11 patients (78.6%) experienced disease progression. Safety data showed one patient with grade 3 adrenal insufficiency and one patient died from liver failure. Due to the observed increase in new metastases and tumor growth compared to historical cohorts, this study was terminated. Hence, caution may be needed when advancing Bintrafusp alfa and similar targets without guiding biomarkers, partly due to the inherent anti-tumor effects of TGF-β signaling in colorectal cancer.

Pancreatic Cancer (PDAC)

TGF-β is a known driver of immune evasion in PDAC, and TGF-β inhibition has been shown to enhance the response to ICIs in preclinical disease models. Consequently, combined TGF-β and PD-1/PD-L1 inhibition is currently under clinical investigation in PDAC.

A phase 1b study (NCT02734160) explored the combination of Galunisertib and anti-PD-L1 antibody Durvalumab in 32 patients with metastatic PDAC. Results indicated one patient (3.1%) achieved a partial response, seven patients (21.9%) had stable disease, with a disease control rate of 25%. The median overall survival was 5.72 months, and the median progression-free survival was 1.87 months. Overall, the treatment was well-tolerated, with five patients (15.6%) experiencing grade 3/4 treatment-related adverse events.

Data on Bintrafusp alfa in PDAC are limited, with a recent phase 1 trial (NCT02517398) including 5 PDAC patients among 19 heavily pretreated cancer patients. Only one MSI-H, locally advanced PDAC patient showed a partial response lasting 10.5 months before disease progression. Several other trials are ongoing, but results have not been reported yet.

Biliary Tract Cancer

Several studies are currently exploring the inhibitory effects of TGF-β and PD-1/PD-L1 in biliary tract cancers, with most involving Bintrafusp alfa. Phase 1 data from an early clinical trial (NCT02699515) in 30 pretreated biliary tract cancer patients showed an objective response rate of 20% (6/30), with median progression-free and overall survival of 2.5 and 12.7 months, respectively. In terms of safety, 11/30 (36.7%) patients experienced grade 3 or worse adverse events, including three treatment-related deaths due to septic shock or interstitial lung disease.

However, in a phase 2 study involving 159 patients (NCT03833661), the objective response rate dropped to only 10.5%. This marked the first major failure of Bintrafusp alfa in a large-scale trial. Another phase 2 trial (NCT04066491) compared Bintrafusp alfa with gemcitabine and cisplatin as a first-line treatment for locally advanced or metastatic biliary tract cancer. However, Bintrafusp alfa failed to significantly improve outcomes compared to the control group receiving gemcitabine and cisplatin. Therefore, this study was also terminated. Despite these setbacks, some similar studies are still ongoing.

Gastric and Esophageal Cancer

Several ongoing clinical trials are also evaluating the role of TGF-β and PD-1/PD-L1 in gastric and esophageal cancers. One such study is a multi-tumor phase 1 clinical trial (NCT02699515) evaluating monotherapy with Bintrafusp alfa, including 31 patients with recurrent, locally advanced, or metastatic gastric/gastroesophageal junction cancer. Results showed that 7/31 (22.6%) patients had objective responses, with 2 cases (6.5%) achieving complete responses. Bintrafusp alfa was well-tolerated overall.

Another phase 1 pan-cancer trial (NCT02517398) is currently assessing esophageal cancer patients. In this study, 30 patients with esophageal adenocarcinoma received Bintrafusp alfa treatment after chemotherapy failure. The report showed an efficacy rate of 20% (6/30), with a median duration of response ranging from 1.3 to 8.3 months. In terms of safety, 19/30 (63.3%) patients experienced treatment-related adverse events, with 7/30 (23.3%) patients experiencing grade 3 toxicity, and no grade 4 or 5 toxicity events were reported.

Immune-Related Adverse Events

While TGF-β inhibitors like Bintrafusp alfa can enhance the anti-tumor immune response, they can also increase the risk of immune-related adverse events (irAEs) when combined with ICIs. This is particularly evident in patients with pre-existing autoimmune diseases or conditions. In clinical trials, these irAEs have included colitis, dermatitis, hepatitis, hypophysitis, nephritis, and pneumonitis, among others.

Managing these irAEs requires vigilant monitoring and a multidisciplinary approach involving oncologists, rheumatologists, gastroenterologists, and other specialists. Treatment typically involves immunosuppressive agents such as corticosteroids and immune checkpoint blockade discontinuation, which may impact anti-tumor efficacy. Thus, there is a delicate balance between enhancing the anti-tumor immune response and managing irAEs.

TGF-β Resistance

Tumor resistance to TGF-β inhibition is a significant challenge in clinical translation. Preclinical models have shown that many tumors can develop resistance to TGF-β blockade over time. Mechanisms of resistance include alternative signaling pathways, secondary mutations, and altered tumor microenvironments. Consequently, patients may initially respond to TGF-β inhibitors but eventually relapse due to the emergence of resistant tumor clones.

To address resistance, researchers are exploring combination therapies involving TGF-β inhibitors and other targeted agents, chemotherapy, or radiation therapy. These approaches aim to target multiple signaling pathways and create a more hostile tumor microenvironment, thus enhancing the therapeutic effect and potentially delaying resistance development.

Patient Selection and Biomarkers

Patient selection remains a critical challenge in TGF-β inhibitor trials. Identifying the right patient population that will benefit most from TGF-β blockade is essential. Currently, there are no validated predictive biomarkers to guide patient selection for TGF-β inhibitor therapy.

Several ongoing studies are exploring potential biomarkers, such as tumor TGF-β expression levels, tumor-infiltrating lymphocytes, mutational burden, and specific genetic alterations. However, these biomarkers are not yet widely accepted or validated, making it challenging to identify the most appropriate patients for TGF-β inhibitor treatment.

Conclusion

Clinical translation of TGF-β inhibitors in combination with PD-1/PD-L1 inhibition remains a complex and evolving field with significant challenges. While preclinical studies have demonstrated the potential for enhanced anti-tumor activity, clinical trials have not consistently replicated these results. Challenges include the management of immune-related adverse events, overcoming resistance, and identifying predictive biomarkers for patient selection.

Despite these challenges, research in this area continues to advance, and new strategies are being explored to improve the efficacy and safety of TGF-β inhibitor therapy. As our understanding of the complex role of TGF-β in cancer continues to grow, there is hope that innovative approaches will lead to more successful clinical outcomes in the future.

What Are the Challenges in Clinical Translation of Targeting TGF-β?

(source:internet, reference only)

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