Unlocking the Potential of Immunotherapy

Tumors are classified on a spectrum:

  • Immune inflamed (or T-cell inflamed): T cells are present but unable to kill tumor cells because of inhibitory signals from the tumor
  • Immune excluded: T cells are present but locked out and therefore can’t efficiently infiltrate to kill tumor cells
  • Immune desert: T cells are absent

Many immune-inflamed tumors are responsive to first-generation PD-1 inhibitors, which block the inhibitory signals from the tumor, thereby activating T cells to kill tumor cells. The immune-excluded subtype, however, is the largest immune phenotype in tumors such as colorectal, ovarian, and non–small cell lung cancer. Across tumors, it consistently represents a larger proportion of patients versus immune inflamed. Because immune-excluded tumors lock T cells out of the tumor microenvironment (TME) via unique immunosuppressive characteristics, first-generation PD-1 inhibitors are often minimally effective in treating these cancers.

Immune-excluded tumors present a significant unmet need.

ImmunoGenesis seeks to unlock the potential of immunotherapy for the large percentage of patients who present with immune-excluded tumors.

While traditional approaches and new combination treatments continue to disappoint, ImmunoGenesis endeavors to revolutionize treatment for immune-excluded tumors. With a deliberate drug development strategy based in these tumors’ pathology, ImmunoGenesis is creating sophisticated therapies that target key mechanisms of immune resistance.

Key Mechanisms of Immune Resistance

  • T cells excluded from the TME by immunosuppressive cells
  • Immunosuppressive cells dominate the TME
  • Tumor hypoxia limits T-cell access
  • Lack of activated T cells

Mechanisms of Immune Exclusion

T cells can't access immune-excluded tumors. The few that do are quickly shut down.

In certain tumors, such as prostate and pancreatic, hypoxia is a driving force in limiting T-cell access.

Abbreviations: CAF, cancer-associated fibroblast; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage.

Combinations and bispecifics have not been able to overcome immune exclusion

Development has focused on combinations or bispecifics with first-generation PD-1 inhibitors as the base, but the low success rate for this combination reveals their limitations. Thousands of combination trials have been conducted, with few showing success.

What if you could overcome multiple of these exclusion mechanisms?

IMGS-001 could make it happen.

Re-envision the treatment starting point

IMGS-001

A single drug designed to break the barrier to unlock T cells and have optimal PD-1 blockade.

Cytotoxic immune checkpoint inhibitor (ICI) multifunctional mechanism:

  • Effector function to remove immunosuppressive stroma
    and
  • PD-1 pathway blockade equivalent to a PD-1/PD-L1 combination

IMGS-001 takes down the barrier and kills immunosuppressive cells

T cells can't access immune-excluded tumors. The few that do are quickly shut down.

IMGS-001 breaks the immune-excluded wall. T cells enter and can remain active.

IMGS-001 activates the invading T cells through the other arm of its mechanism: full PD-1 pathway blockade.

Abbreviations: CAF, cancer-associated fibroblast; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage.

Our lead program, IMGS-001, is a cytotoxic ICI that re-envisions the starting point for immune-excluded tumor treatment. It’s a novel PD-L1/PD-L2 antibody designed with effector function to kill the immunosuppressive cells in the TME. Current first-generation PD-1 inhibitors lack efficacy as monotherapy in immune-excluded tumors, so combinations using them haven’t been effective in this setting. IMGS-001 tackles T-cell exclusion and the PD-1 inhibitory signal in a single molecule, offering potential efficacy as a monotherapy and a foundation for future combinations.

In preclinical models, IMGS-001 depleted key immunosuppressive cells, expanded dendritic cells, and drove increased proliferation of T cells. IMGS-001 has the potential to drive differentiated efficacy and provide a strong therapeutic foundation for carefully designed add-on therapies to further optimize outcomes for patients with immune-excluded tumors.

Preclinical Highlights

In murine models of immune-excluded tumors (B16-PDL2), IMGS-001 cured 50% of mice and drove >90% tumor growth inhibition, while the PD-1 comparator showed no curative benefit.

Clinical Highlights (NCT06014502)

Completed the initial dose-escalation phase up to the targeted maximum dose with no dose-limiting toxicities

Reverse hypoxia in the TME

IMGS-101 (evofosfamide)

The unregulated growth of cancers creates regions of hypoxia (little to no oxygen) that drive tumors to

  • Adapt metabolically and become more aggressive
  • Condition their TME to evolve multiple mechanisms of immune suppression

Hypoxia is a dead end for any T cells coming to attack the tumor, because these regions are packed with immunosuppressive cells and lack oxygen and other essential nutrients required to mount an anti-tumor immune response. In difficult-to-treat cancers like pancreatic, prostate, and head and neck, hypoxia plays a critical role in resistance to immune checkpoint antibody therapy.

IMGS-101 (evofosfamide) is a novel drug using a unique approach to reducing hypoxia in solid tumors. Evofosfamide is a “smart” drug that activates only under the low-oxygen conditions found in cancers. It remodels the TME to restore oxygenated blood supply, reduces hypoxia and associated immunosuppression, and restores the capacity of T cells to enter the tumor and remain active within it. IMGS-101 conditions otherwise insensitive cancers to respond to immune checkpoint therapy by allowing tumor-specific T cells to enter and accumulate within them.

This approach reflects Dr. Curran's vision to identify the pivotal sources of immune resistance in cancer and then target them to restore sensitivity to immunotherapy. IMGS-101 has already been studied in more than 1,600 patients, with early clinical data demonstrating encouraging activity. The program has advanced into a phase 1/2 clinical trial designed to sensitize otherwise resistant cancers to immune destruction.

IMGS-101 reverses hypoxia

ImmunoGenesis is investigating the use of IMGS-101 in combination with immune checkpoint blockade (combined with PD-1 and CTLA-4 inhibition) to make solid tumors more accessible to immune clearance.

Block immune checkpoint signals and attack the suppressive TME

IMGS-203

ImmunoGenesis has developed a potent stimulator of interferon genes (STING) agonist, IMGS-203. This molecule has demonstrated promising preclinical efficacy in difficult-to-treat tumor settings, including spontaneous glioblastoma multiforme (GBM) in canines. The company is conducting IND-enabling activities for a phase 1 GBM trial.

IMGS-203 can potently activate the STING pathway, which can enhance T-cell priming and infiltration and reprogram the TME toward an inflammatory, tumor-suppressive phenotype.

Clinical Programs

Our lead program, IMGS-001, is currently enrolling patients in a phase 1a/b clinical trial (NCT06014502).

Our second clinical program, IMGS-101 (evofosfamide), is currently enrolling patients in a phase 1/2 clinical trial (NCT06782555).

Our Vision

By harnessing cutting-edge science, the ImmunoGenesis pipeline is designed to redefine the treatment landscape for immune-excluded tumors, re-envision existing immunotherapy treatment approaches, and ultimately, provide necessary treatments for patients left behind by first-generation PD-1 inhibitors.

Fuel the science