Immunotherapy on hold?

#ColorectalCancer #Immunotherapy #ICI #XL888 #CombinationTherapy  


Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, especially in advanced stages where treatment options become limited. The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed the treatment landscape of several solid tumors. In CRC, these treatments have shown remarkable efficacy in patients with microsatellite instability (MSI) or mismatch repair deficiency (dMMR), leading to prolonged and sometimes durable responses.  

However, these hypermutated forms represent only about 5% of metastatic colorectal cancers (pMMR), leaving the vast majority of patients without real benefit from ICIs. In this context, it becomes essential to develop combination strategies capable of recruiting or activating immune cells in these patients.  

This study explores the safety, feasibility, and immunologic impact of an innovative combination. Pembrolizumab, an anti-PD-1 antibody, is paired with XL888, an inhibitor known to regulate the stability of several proteins involved in tumor growth and immune response. This combination could reduce resistance mechanisms, remodel the tumor microenvironment, and enhance ICI response in patients with advanced CRC who are refractory to standard treatments.  

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Activating immunity, overcoming resistance?  

The study included two patient groups. Fourteen patients with advanced gastrointestinal cancers were enrolled in a dose-escalation phase to evaluate the tolerability of XL888 at doses of 45, 60, and 90 mg in combination with pembrolizumab. The 90 mg dose was selected as the recommended dose for the next phase.  

A subsequent expansion cohort of 16 patients with advanced pMMR colorectal cancer received pembrolizumab (200 mg) plus XL888 (90 mg). Treatment continued until disease progression or the emergence of adverse events.  

Evaluation criteria included clinical tolerability and in-depth immune analyses. Researchers assessed plasma cytokines and circulating immune cells to evaluate systemic immune response. In parallel, liver metastasis biopsies were examined using CyTOF and mIHC to assess the combination’s effect on the tumor microenvironment.

Clinically, results were modest. No objective responses were observed, and 25% of patients experienced disease stabilization. However, treatment was well tolerated, with only 12.5% experiencing grade 3 or 4 adverse events, confirming the combination’s feasibility.  

Immunologic analyses revealed significant immune system changes. In liver metastases, a decrease in CD68+ macrophages and IL-6+ cells suggested a reduction in local inflammation. In the blood, B and T lymphocytes decreased while several inflammatory cytokines increased, indicating systemic immune activation.  

Despite these encouraging biological signals, the liver tumor microenvironment remained poorly infiltrated by lymphocytes, limiting the effectiveness of PD-1 blockade. These results demonstrate real immune modulation but insufficient on its own to trigger a significant antitumor clinical response in this context.  

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An immune awakening… but no response?  

pMMR colorectal cancer remains largely unresponsive to immunotherapy, particularly in the presence of liver metastases, where the tumor microenvironment is notably poor in infiltrating T lymphocytes (TILs). This lack of local immune response is a major barrier to ICI efficacy, despite their proven effectiveness in other tumor types.  

The primary challenge is to remodel this immunosuppressive environment to promote T-cell infiltration and activation, thus restoring sensitivity to ICIs in pMMR tumors.  

This study investigates the potential of the XL888-pembrolizumab combination to reactivate immune responses in pMMR colorectal cancer by targeting resistance mechanisms related to the stability of tumor and immune proteins.  

While observed clinical efficacy was limited, immunological signals confirmed real modulation of the immune system, both within tumors and systemically. This biological response indicates an active pharmacological effect, though insufficient to induce tumor regression in this setting.  

Despite its limitations, this study provides valuable data on the feasibility and biological effects of this combination. It lays the groundwork for strategies aimed at extending the benefits of immunotherapy to previously non-responsive patients.  

Future trials could target patients with lung metastases, which typically have more immune cell infiltration, or incorporate additional immune-stimulating agents to further enhance T-cell activation. Earlier integration into the treatment sequence, particularly in synergy with chemotherapy or radiotherapy, may also boost the effectiveness of this approach.  

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