A Phase I/II clinical trial has been initiated to evaluate a hypoxia-modifying agent, IMGS-101 (evofosfamide), in combination with checkpoint inhibitors for the treatment of adult patients with advanced cancers. The first patient was dosed at the University of Texas MD Anderson Cancer Center. The open-label study will focus on patients with metastatic castration-resistant prostate cancer (mCRPC), HPV-negative squamous cell carcinoma of the head and neck (SCCHN), and pancreatic cancer. The trial includes dose escalation and expansion phases to assess the pharmacokinetics, efficacy, anti-tumor activity, and safety of the combination therapy.

The trial addresses a major obstacle to cancer immunotherapy by targeting hypoxia, a condition that restricts T-cell infiltration and diminishes immune responses. By counteracting hypoxia, this approach may facilitate T-cell access to tumors, thereby boosting the efficacy of checkpoint inhibitors and potentially improving outcomes in these challenging cancers.

Hypoxia, or low oxygen levels, is a common characteristic of solid tumors, including prostate cancer. In mCRPC, hypoxia plays a significant role in:

Promoting Aggression and Metastasis: Hypoxic conditions select for cancer cells with increased metastatic potential. Hypoxia induces the expression of genes involved in angiogenesis (formation of new blood vessels), allowing tumors to grow and spread. It also upregulates factors that promote epithelial-mesenchymal transition (EMT), a process that enables cancer cells to detach from the primary tumor and invade surrounding tissues.

Therapy Resistance: Hypoxia contributes to resistance to various cancer therapies, including radiation and chemotherapy. It can reduce the effectiveness of radiation by decreasing the production of reactive oxygen species, which are crucial for radiation-induced cell death. Hypoxia can also reduce the sensitivity of cancer cells to chemotherapeutic drugs.

Immune Evasion: Hypoxia impairs the function of immune cells, particularly T cells. Hypoxic environments within tumors can inhibit T-cell infiltration, suppress their cytotoxic activity, and promote the expression of immune checkpoint molecules, allowing cancer cells to evade immune destruction.

The treatment has shown promise in preclinical models and a Phase I trial, demonstrating early signs of synergy with checkpoint inhibitors by restoring T-cell functionality. The goal is that by reversing hypoxia, this approach prepares tumors to be more responsive to checkpoint inhibition.

Clinical trial.