Nectin Therapeutics Collaborates with Merck on Cancer Treatment

March 27, 2023 - Earlier this year, Nectin Therapeutics Ltd, a clinical biotechnology company, announced a collaboration with Merck, a leading global pharmaceutical company, to develop a treatment regimen for cancer patients. The clinical trial combines a novel anti-PVR antibody treatment, NTX1088, and Keytruda (pembrolizumab), an anti-PD1 therapy. While the study is still in early-stage clinical trials, the researchers hope the drug combination will effectively treat advanced and metastatic solid tumors.

Solid Tumor Statistics

The National Cancer Institute (NCI) defines a solid tumor as a mass of tissues that do not have any liquid or cystic parts. Although solid tumors can be benign or malignant, roughly 90% of adult cancers present with a solid tumor. According to ThermoFisher, solid tumors are linked to approximately 40% of cases in pediatric patient populations. Cancers, including sarcomas, carcinomas, and lymphomas, may involve solid tumors; leukemias rarely cause solid tumors.

According to the CDC, in 2019, 1,752,735 people in the United States were diagnosed with new cancer. Additionally, over half a million individuals, 599,589, died of cancer in 2019, accounting for roughly 439 new cases and 146 deaths per 100,000 individuals.

More recent statistics by the NCI estimate that the number of new cancer cases in 2022 rose to nearly two million, or exactly 1,918,030 new cases. In addition, the estimated number of cancer-related deaths in 2022 is 609,360.

Beyond incidence and deaths, the NCI states that the average five-year survival rate of all cancers between 2012 and 2018 was less than 70%, for an exact estimate of 68.1%. Immunotherapy treatments and immuno-oncology have become critical tools for treating cancers with advanced solid tumors. Although many patients will survive their cancer diagnosis, many types of cancer don’t respond to treatment, causing researchers to search for new treatment methods.

PD-1 Blockers

Healthcare researchers and oncologists have recently used monoclonal antibody (MAB) therapies to target immune checkpoints. According to the American Cancer Society (ACS), MAB treatments focus on immune activation by promoting antitumor activity using a patient’s own immune cells.

Programmed cell death protein 1 (PD-1) proteins are expressed on the surface of immune cells. They act as regulators for T Cells, preventing them from attacking other cells when they attach to program death ligand 1 (PDL-1) on the cell surface. Although this mechanism of action usually prevents the immune system from attacking healthy cells in the body, in some cancer cases, PDL-1 is overexpressed on the surface of a tumor, allowing the tumor to grow uncontrollably.

PD-1 and PDL-1 inhibitors, in the form of antibody–drug conjugates, can block the binding between the two proteins, allowing the immune system to attack cancerous cells properly.

Poliovirus Receptor Proteins

A Cellular and Molecular Biology study explained that the poliovirus receptor, sometimes called PVR or CD155, significantly mediates the immune response.

PVR expression on the surface of tumor cells has been linked with cancer progression, acting as a biomarker for tumor growth. An article published in Cancer Research notes that high levels of PVR expression on tumor cells are connected to a lower sensitivity to anti-PDL1 therapy. In contrast, low levels of PVR expression indicate slower tumor growth.

PVR proteins can either bind to DNAM1 proteins to activate immune cells or T cell immunoreceptor proteins with Ig and ITM domains (TIGIT) for immune system inhibition.

In many cancers, DNAM1 expression is downregulated, leading most PVR proteins to bind to TIGIT. According to an article published in Translational Oncology, “TIGIT interacts with its major ligand poliovirus receptor (PVR), also called cluster of differentiation 155 (CD155), to exert its immunosuppressive effects.” This suppresses the immune response by T and NK cells.

“By binding to receptors on immune cells, PVR sends a signal from the cancer cells into the immune cells to not attack the cancer cells,” explained Keren Paz, PhD, Chief Development Officer of Nectin Therapeutics. “In a way, it induced a situation where the immune system in the body cannot attack cancer cells. Then, cancer cells remain there and develop tumors around them.”

NTX1088

While many drugs have targeted PD1/PDL1, fewer have focused on inhibiting PVR proteins. Nectin therapeutics is studying a new PVR antibody to treat cancers resistant to PD1/PDL1.

“NTX1088 is a monoclonal antibody directed against a target or a protein called PVR, or poliovirus receptor,” explained Paz.

NTX-1088 binds the PVR, preventing PVR from binding to TIGIT on immune cells, which may suppress antitumor immunity.

“It eliminates the negative effect on the immune system so that the immune cells and the immune system can attack and eliminate cancer cells,” she continued. “Several other treatments work through similar mechanisms, but no other drug acts identically.”

Comparison to Drugs on Market

“Other drugs that exist right now — drugs that the FDA and others already approve to treat cancer patients or drugs that are currently in clinical development — interfere with the interaction between these checkpoint inhibitors and their receptors to release the blockade that those immune checkpoint inhibitors (ICIs) induce on the immune system,” noted Paz.

NTX-1088 works similarly with one added mechanism. Beyond releasing blockers, this treatment also activates activator proteins.

Paz revealed that the drug could be used as a monotherapy, with tumors in preclinical in vitro animal models being eliminated with NXT-1088 alone. However, some tumors were not effectively treated with NTX-1088. At that point, clinical researchers added Keytruda to the treatment regimen, which improved the elimination of tumor cells.  

NTX1088 and Keytruda

“When we combine Keytruda with NTX-1088, elimination of the tumor in animals was achieved,” explained Paz. “In a way, there is an additive effect, perhaps even a synergistic effect, when we combine the two drugs.”

Paz and researchers at Nectin hypothesize that NTX1088 can be used as a monotherapy for patients who are not expected to respond to Keytruda.

Beyond that, Paz and her team believe that patients with tumors that could potentially respond to Keytruda and other PD-1 and PD-L1 inhibitors but are not could benefit from a combined therapy of PD-1 or PD-L1 inhibitors with NTX-1088.

Phase 1 Clinical Trial

While the theories developed by Paz and her team are based on extensive preclinical research, they will be working on human clinical trials to prove their theories. The phase 1 trial, slated to start soon, is expected to recruit roughly 90 patients to be treated at the University of Texas MD Anderson Cancer Center.

“We're going to start with dose escalation because this drug is first-in-human but also first-in-class,” added Paz. “Being the first to develop a drug that targets PVR, we have to learn everything about the drug and the class of drugs.”

Considering the limited information available on this class of drugs, the clinical researchers plan to start with a very low dose of the medication and escalate the amount slowly, allowing researchers to assess the medicine’s safety closely. Once researchers determine the effective dose of the medication, they can monitor the efficacy and utility of the drug.

“The effective dose can be the maximal dose with no side effects. We don't even think that we're going to get to that level because we don't expect any side effects based on the work we've done in animals and on the profile of the target in normal tissues versus tumors,” she noted.

Throughout the clinical trial, the researchers plan to monitor the drug’s safety with traditional safety measures. Beyond that, the research team, led by Sarina A. Piha-Paul, MD, will monitor tumor markers in circulation and image patients to track tumor progression.