At the AACR Annual Meeting 2023 in Orlando, Purple Biotech, a clinical-stage company developing first-in-class therapies that address tumor immune evasion and drug resistance, presented exciting new results for NT219, a novel small molecule dual inhibitor of IRS1/2 and STAT3 escape mechanisms.
The findings demonstrate the potential of NT219 to work synergistically with either anti-PD1 or anti-CTLA4 drugs to reprogram the immune profile in the tumor microenvironment (TME) and convert resistant tumors to responders to Immune Checkpoint Blockage (ICB) therapies.
The study was spearheaded by researchers at The University of Texas MD Anderson Cancer Center. These results provide new hope for cancer patients and offer a promising pathway to overcoming tumor resistance.
NT219 has demonstrated remarkable potential in the fight against melanoma. In-vitro studies have shown that NT219 induces a significant expression of PDL1 in melanoma cells, while in-vivo studies have revealed a synergistic effect with anti-PD1 therapy in the inhibition of tumor growth.
Notably, the induction of PDL1 by NT219 was much higher in the ICB-resistant melanoma strain compared to ICB-sensitive cells, indicating the potential to re-sensitize refractory tumors to anti-PD1 therapy. In this way, NT219 has the potential to be an invaluable tool in the fight against melanoma.
In immunocompetent mice bearing stubborn ICB-resistant tumors, NT219 treatment in combination with anti-PD1 or anti-CTLA4 therapies not only activated CD8 cytotoxic T cells, NK cells and other immune cells, but also decreased infiltration of immunosuppressive populations, including regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages. These powerful effects were not seen with either therapy alone, highlighting the potential of NT219 to be a game-changer in fighting cancer.
In an exciting new development, the combined use of NT219 and anti-PD1 has been shown to induce significant tumor growth inhibition of ICB-resistant tumors, even when used on their own they had no effect. This synergistic effect is a promising discovery for future cancer treatments.
The ICB-resistant clone of the same origin melanoma cells displayed heightened activation of both IRS1 and STAT3 in comparison to its ICB-sensitive counterpart. However, when treated with NT219, both clones experienced a marked drop in IRS1 and STAT3 phosphorylation, indicating a long-lasting effect of the drug on these proteins, which are known to contribute to drug resistance.
The process by which tumors become resistant to many cancer drugs can be devastating, robbing patients of hope and precious time with their families. To combat this, Purple Biotech’s VP R&D Hadas Reuveni, PhD, suggests that combining ICB with NT219 may be a promising strategy to reprogram the immune profile of the TME, aiming to turn ‘cold’ tumors ‘hot’ and re-sensitize resistant tumors to anti-PD1 therapy. This could potentially lengthen the duration of treatment and broaden the patient population who may benefit from these treatments.
NT219 is an innovative, dual inhibitor small molecule that targets both IRS1/2 and STAT3. In a Phase 1/2 clinical trial, it is being tested as a monotherapy for solid tumors, and in combination with cetuximab to treat recurrent and metastatic squamous cell carcinoma of the head and neck and colorectal adenocarcinoma.
Following the dose-escalation phase, an expansion trial of NT219 in combination with cetuximab will be conducted in patients with recurrent and metastatic SCCHN to determine the recommended Phase 2 dosage.
About Purple Biotech
Purple Biotech Ltd. (NASDAQ/TASE: PPBT) is a clinical-stage company on a mission to revolutionize cancer treatments. Our oncology pipeline includes NT219, CM24, and IM1240, each of which have the potential to overcome tumor immune evasion and drug resistance.
NT219 is a dual inhibitor, novel small molecule that targets IRS1/2 and STAT3, and is currently being studied as a monotherapy treatment for solid tumors and in combination with cetuximab for SCCHN and CRC. CM24, a humanized monoclonal antibody that blocks CEACAM1, has been combined with anti-PD-1 checkpoint inhibitors and chemotherapy in a Phase 2 study for the treatment of pancreatic ductal adenocarcinoma.
Lastly, IM1240 is a preclinical, conditionally-activated tri-specific antibody that engages both T cells and NK cells to mount a localized immune response in the tumor microenvironment. We are proud to be based in Rehovot, Israel, and are committed to bringing innovative and life-saving treatments to cancer patients around the world.