New I-O Targets Herald a Decade of Drugging the Undruggable (Jan 16)

New I-O Targets Herald a Decade of Drugging the Undruggable

Anat Cohen-Dayag_Compugen

Compugen President and CEO Anat Cohen-Dayag, Ph.D./courtesy of Compugen

There’s a revolution unfolding in cancer therapeutics as researchers learn to harness the immune system to fight even the most stubborn tumors.

Three key immune checkpoints have been established during the past decade. In 2011, CTLA-4 was validated as an immune checkpoint when the FDA approved Bristol Myers Squibb’s Yervoy (ipilimumab) in metastatic melanoma. This approval was followed in 2014 by PD-1 when the regulator greenlit Merck’s Keytruda (pembrolizumab), also in melanoma.

Last year, it was BMS’s turn again to make history with the approval of Opdualag, a fixed-dose combination of the LAG-3-blocking antibody relatlimab and the PD-1-blocking antibody nivolumab.

“This past decade saw the untreatable become treatable as we gained momentum on some of the most challenging types of cancer,” said Yaron Daniely, Ph.D., partner at Israeli investment firm aMoon, head of aMoon Alpha and chair of the oncology session at the upcoming Biomed Israel conference. “I believe this will be a decade of turning the undruggable into the druggable.”

Yaron Daniely_aMoon
Yaron Daniely, Ph.D.

There is still much work to do, however.

“The revolution brought about by PD-1 inhibitors is only curtailed by the sophistication of tumor cells and their ability to evade these agents, leading to limited response rates in the population,” Daniely said.

There is perhaps no more important I-O checkpoint, particularly in non-small cell lung cancer, than PD-1/PD-L1. PD-L1 is expressed on several tumor cells and its receptor, PD-1, is highly expressed by T-cells. Their interaction reduces the ability of T-cells to signal the immune system to fight the tumor.

PD-1/PD-L1 inhibitors have shown durable responses in lung cancer, kidney cancer and melanoma. However, tumors have an uncanny ability to develop resistance in order to survive. Clinical research has shown that more than 50% of patients with tumors that highly express PD-L1 might not respond to these therapies. 

In fact, the overall response to PD-1 and PD-L1 inhibitors is just under 20%, according to an aggregate of clinical trials published in Frontiers in Oncology in 2021. This means there is still significant unmet need.

For Daniely, the nectin family of proteins is one of the most exciting targets currently being evaluated as they are “clear culprits in the ability of tumors to evade immune checkpoint control.” 

“I believe that as new data continue to accumulate on TIGIT, the interest in this protein family will increase and we will hopefully see clinical proof of concept for their validity in attaining more robust response rates in patients,” he said.

Traversing the PVR-TIGIT Axis

An important emerging checkpoint, TIGIT – an immune receptor present on some T cells and NK cells – is highly expressed on a wide range of solid tumors and hematological malignancies.

In January 2021, Genentech (Roche)’s tiragolumab became the first anti-TIGIT therapy to receive Breakthrough Therapy Designation from the FDA. Tiragolumab was granted BTD in combination with Tecentriq for PD-L1-high NSCLC.

PVR is a tumor-expressing protein involved in a significant number of interactions within the immune system. TIGIT competes with immunoactivator receptor CD226 (DNAM-1) for the same set of ligands: CD155, or poliovirus receptor (PVR) and CD112 (Nectin-2 or PVRL2).

Ofer Mandelboim, Ph.D. and Pini Tsukerman, Ph.D., scientific advisor and CSO respectively at Nectin Therapeutics, were among the first to uncover the role of the PVR-TIGIT axis in immuno-oncology. The breakthrough, made at the Hebrew University of Jerusalem, led to the founding of Nectin in 2017.

The company’s lead candidate is NTX1088, a first-in-class PVR blocker intended to treat patients with locally advanced and metastatic solid tumors.

While it was once believed that blocking PVR would be disadvantageous due to its interface with DNAM-1, Mandelboim’s lab discovered that the interaction is short-lived and not actually needed for DNAM-1 expression.

Fabian Tenenbaum_Nectin Therapeutics
Fabian Tenenbaum

In an interview with BioSpace, Nectin CEO Fabian Tenenbaum said what makes PVR blockade unique is its ability to activate both antagonistic and agonistic approaches.

“By blocking PVR, we block its immune checkpoint inhibition activities against TIGIT, CD96 and a couple of other receptors… but really what differentiates PVR is its ability to bring to bear an agonistic approach for the immune system,” he said. This is because blocking PVR expression brings DNAM-1, a functional glycoprotein expressed on immune cells that is critical for cell activation – back to the surface.

Nectin has seen these antagonistic and agonistic benefits in preclinical models and hopes to replicate them in patients. The first patient was dosed in a Phase I clinical trial in late November.

PVRIG Plus TIGIT – a Winning Combination?

As in other therapeutic spaces, artificial intelligence and machine learning (AI/ML) is emerging as a game changer in I-O. In this instance, it enabled Tel Aviv-based Compugen to uncover PVRIG, a previously unidentified checkpoint.

PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2.

Compugen’s COM701, which targets PVRIG, is the first antibody to enter Phase I studies where both candidate and target were discovered by the same company.

Results from a Phase I trial presented at the ESMO Immuno-Oncology Congress 2022 showed the experimental therapy in addition to Opdivo (nivolumab) and anti-TIGIT therapy BMS-986207 demonstrated durable anti-tumor activity and immune activation in patients with platinum-resistant ovarian cancer.

In November, Compugen presented data showing that COM701 in combination with Opdivo yielded a 12% overall response rate in third-line microsatellite stable (MSS) colorectal cancer patients with liver metastases.

Anat Cohen-Dayag2
Anat Cohen-Dayag, Ph.D.

Compugen President and CEO Anat Cohen-Dayag, Ph.D. told BioSpace the company believes these responses are mediated by blocking PVRIG with COM701.  

Cohen-Dayag explained that PVRIG, an immune checkpoint in the DNAM-1 axis, is an important signaling pathway in T cell and natural killer (NK) cell function.

The company’s research and clinical data “suggest that blocking PVRIG together with TIGIT and PD-1…could further enhance clinical responses seen in inflamed indications like NSCLC,” as well as less inflamed ones like MSS colorectal cancer.

A cold tumor, or one with very few immune cells in the tumor microenvironment, MSS colorectal cancer is the second leading cause of cancer deaths in the U.S.

This is not the first time Compugen has identified a new target. In 2009, at nearly the same time, both Compugen and Genentech published literature outlining the role of TIGIT as an immune checkpoint.

In November 2021, Compugen presented data from its anti-TIGIT antibody COM902. It was the first data showing signals of anti-tumor activity elicited by an IgG4 anti-TIGIT antibody with low Fc effector function.

Biond and Sanofi Target ILT2

Biond Biologics, based in Misgav, Israel, is tackling a different target: immunoglobulin-like transcript 2 (ILT2). ILT2 is an inhibitory receptor expressed on T cells, NK cells and some myeloid cells. It binds to human leukocyte antigen G (HLA-G) which is overexpressed in many tumors, effectively blocking the anti-tumor effects of T cells and NK cells.

Biond’s lead asset, BND-22, selectively binds to ILT2 and blocks its interaction with HLA-G. In preclinical studies, the antibody has shown a broad anti-tumor effect by activating CD8+ lymphocytes and NK cells and blocking the ILT2-mediated “don’t eat me” signal on macrophages.

Tehila Ben_Moshe_Biond Biologics
Tehila Ben Moshe Ph.D.

Biond Co-founder and CEO Tehila Ben Moshe Ph.D. told BioSpace that this target’s uniqueness lays in its interplay with both the innate and adaptive immune system. She called it a “multi-immune checkpoint inhibitor” because it acts on multiple cells in different ways.

In ex vivo studies, Biond collected biopsies and blood samples from patients across hospitals in Israel’s centralized healthcare system. Medical records in Israel have been digitalized for more than two decades, enabling valuable access for researchers.

In this case, it enabled Biond to study the relationship between immune cells and tumor cells in a single patient.

“We learned the relationship between [the patient’s] own immune cells, macrophages, lymphocytes and the tumor cells,” Ben Moshe said.

Results from these studies intrigued Sanofi so much that the French pharmaceutical put up a potential $1 billion-plus in January 2021 to partner on BND-22.

In April of the same year, Biond dosed the first patient in a Phase I trial assessing the asset against select advanced solid tumors.

Emerging I-O targets, pathways and biomarkers will be top of mind at Biomed Israel, the country’s leading international life science and health tech conference, taking place May 16-18 in Tel Aviv. 

 *The Biomed Israel conference facilitated meetings with the aforementioned companies at their labs and offices.