The Yale researcher who discovered the PD-L1 molecule and first showed its role in evasion of tumor immunity has teamed up with a veteran biotech executive to launch a precision oncology startup that has set the ambitious goal of expanding the universe of patients who can benefit from cancer immunotherapy.
Normunity has emerged from stealth mode with its announcement Tuesday of a $65 million Series A financing. Normunity aims to create precision immunotherapies that harness a new class of agents called immune normalizers, which are designed to fight cancer by targeting previously undiscovered mechanisms of immune disruption.
Specifically, the immune normalizers target mechanisms that allow an active and effective immune system into ‘cold’ tumors that are not infiltrated with immune cells, and thus are not recognized by the immune system and resistant to present-day immunotherapies. The company’s first pipeline programs target mechanisms that drive the exclusion of T cells into immune-sensitive tumors, which is the area of biology being investigated by one of several immuno-oncology platforms from the lab of the company’s scientific founder, Lieping Chen, MD, PhD.
“Immune normalizers are an untapped new compartment in the immune system. We think there’s a lot of white space here that other folks are not looking at,” Normunity Founding CEO Rachel Humphrey, MD, told GEN Edge. “This is not checkpoint inhibition, which kicks the immune system to switch on. This is not a bispecific antibody, which tries to tug and activate T cells into the tumor milieu. This is not an artificially engineered cellular therapy, which builds on familiar immune targets that have yet to show meaningful efficacy in solid tumors. Most of all, this is not an approach that relies on immune cells to already be in the tumor environment, which is a requirement for all of today’s cancer immunotherapies to work.”
To date, Humphrey said, Normunity has identified at least five potential targets that were discovered through the first of several platforms developed by Chen.
“When things are growing in the body, such as with an infection, you assume the immune system will react to it, and then get rid of it. That’s what normal immune response should be,” explained Chen, who is United Technologies Corp. Professor in Cancer Research and Professor of Immunobiology of Medicine (Medical Oncology) at Yale School of Medicine. “Somehow, cancer finds a way to escape from the immune response, which means that when the immune system tries to get rid of cancer, cancer counterattacks to stop the immune system from fighting cancer.”
Cancer Immunotherapy Pioneer
A pioneer of cancer immunotherapy, Chen conducted the first proof-of-concept study in 1992 showing that the B7-CD28 family of molecules could be the targets for cancer immunotherapy by introducing B7-1 into tumor cells to enhance therapeutic immunity. Seven years later, he discovered the B7-H1 molecule (now known as PD-L1), and successfully demonstrated its role in the evasion of tumor immunity.
In 2002, Chen first showed that blocking the interaction between PD-1 and PD-L1 by monoclonal antibodies improved the immune system’s ability to eliminate tumors. That foundational work established the PD-1/PD-L1 pathway as a target for cancer immunotherapy, and led to the first-in-human clinical trial and subsequent development of Bristol-Myers Squibb (BMS)’s blockbuster cancer immunotherapy Opdivo® (nivolumab). Chen also developed PD-L1 staining as a biomarker to predict treatment outcome.
Normunity isn’t the first company spun out of Yale by Chen. He co-founded Amplimmune, an immunotherapy developer acquired by AstraZeneca in 2013 for up to $500 million ($225 million upfront). Two years later, Chen became scientific founder (and still chairs the Scientific Advisory Board) of NextCure, a developer of first-in-class immunotherapies designed to treat cancer and other immune-related diseases based on identifying positive and negative immune regulators of myeloid cells and T cells. Lead programs include cancer immunotherapies NC318, a monoclonal antibody targeting the immunomodulatory protein Siglec-15 (S15); and NC410, designed to block immune suppression mediated by LAIR-1.
Traditional cancer immunotherapy approaches, from cancer vaccines to cell therapies and cytokines, work by increasing immune response. But simply weaponizing the immune system by making it stronger doesn’t necessarily weaken cancer’s barriers to counter-attacking immune cells, particularly T cells, so cancer continues to progress for many patients.
“We have been working on understanding basic mechanisms of why and how T cells do not even exist in and/or enter into the tumors,” Chen added. “Cancer cells are not just sitting there to be attacked; they actively try to counterattack the immune system. Therefore, we have to understand how cancer goes about creating the barrier to normal immune function, what are the intrinsic problem first. Then we can develop an antibody which will act as a normalizer to enable the immune cell to work, to enter and then to function in the tumor microenvironment.”
Normunity is among numerous startups focused on broadening the potential patient population for cancer immunotherapies.
Last year Bent Jakobsen, PhD, a pioneer of cancer T cell receptor therapy who served as scientific founder of Adaptimmune and Immunocore, launched his own startup, Accession Therapeutics. Based in Oxford, UK, Accession develops immunotherapies by applying its Trocept platform, through which the company engineers viruses that are exclusively directed to cancer cells and carry a transgene coding for one or more antitumor or immune activator drugs.
On October 19, Orionis Biosciences completed a $55 million financing whose proceeds are intended to advance its pipeline of tunable precision medicines, with plans to submit an IND and advance its lead cancer immunotherapy programs into clinical trials. Existing and new investors included Cormorant Asset Management, a series of undisclosed high-caliber investment funds—and Novartis, with which Orionis is partnering to discover small molecule therapeutics, such as protein degraders, across various therapeutic areas through a collaboration of undisclosed value.
‘Perfectly Fresh’
“All of us hope that one of these companies or more will get to where they need to go. And because when the immune system gets it, cures are possible,” Humphrey said. “We’re doing here something that no one has ever done before: Ask the question of the immune system that doesn’t fall into the ‘someone else is doing this.’ This isn’t a me-too approach. It’s perfectly fresh.”
At present, only a limited percentage of cancer patients respond to immunotherapies. Estimates for response rates have ranged from 12.48% as of 2018, according to a study published in JAMA Network Open, to between 20% and 50% according to Johns Hopkins Medicine, which adds that only “15%-20% of patients achieve durable results.”
“One of the multiple platforms in Lieping Chen’s lab reflects a simple truth: None of the therapies, either now approved or in development, will work without immune cells, particularly T-cells, or their engineered constructs, getting into the tumor, period” Humphrey said.
“The obstacles to getting immune cells into the tumor don’t have to be cellular. They can be molecular pathways and mechanisms that are currently unknown,” Humphrey added. “And no one has addressed this fundamental problem before in the way that Lieping and his team has asked it, with very sophisticated and well-heeled and complex technologies and techniques that get to the answer. They ask: Are immune cells locked out of the tumor tissue somehow, and if so, how can the gate be lifted?”
Chen’s lab works with Normunity to identify novel immuno-oncology mechanisms through its own proprietary platforms. The lab interrogates and validates the emerging targets preclinically and clinically, with Normunity translating the target findings into drug candidates using deep experience in antibody drug design and development.
“When he [Chen] says, I think I have something I want to show you, we sit down together,” Humphrey said. “And in parallel–that’s the key part, in parallel—the Normunity discovery team— which is deep and experienced in both drug development and science work hand-in-hand in a complementary way so that the questions that Lieping’s team answers about the nature of the biology are iterated in real time at lab meetings that happen all the time.
“The questions that the Normunity team is asking tend to support the development path in a biotech-side way, all complemented with the answers that his team is getting,” Humphrey added.
Humphrey is a medical oncologist whose 25 years of industry experience includes bringing to market blockbuster cancer drugs for three pharma giants. After overseeing the development of the tyrosine kinase inhibitor Nexavar® (sorafenib) at Bayer, Humphrey went to BMS, where she supervised development of cancer immunotherapy Yervoy® (ipilimumab). She later moved to AstraZeneca, where she led development of its Imfinzi® (durvalumab) and built the company’s immune-oncology department.
More recently, she held CMO positions at companies that included Mirati Therapeutics (back when it was MethylGene), CytomX Therapeutics, and Black Diamond Therapeutics. She sits on the boards of CytomX as well as Pyxis Oncology, Sporos Bioventures, and Xilio Therapeutics.
Shannon is General Partner / East Coast with Canaan Ventures, which led Normunity’s $65 million Series A, with participation by Sanofi Ventures, Taiho Ventures and Osage University Partners. Normunity says proceeds from the financing will enable it to advance its pipeline of immune normalizers into clinical phases, as well as further develop multiple discovery platforms in the Lieping Chen lab that will be designed to pursue additional mechanisms impeding normal anti-cancer immunity.
Undisclosed Targets
Normunity isn’t yet disclosing its targets, the incidence of a given target within a cancer type, or what types of cancers its first treatments will be targeting, though Humphrey said Normunity’s targets are present in multiple cancer types, including common cancers.
Also not being disclosed is Normunity’s timing for bringing its first treatments into the clinic, or the duration of its financial “runway” created by its Series A financing.
“I can say we have plenty of money now to achieve the following: At least one, possibly two drug candidates to IND and ready to enter the clinic, and additional drug candidates to IND- enabling studies,” Humphrey said.
Normunity maintains research operations at West Haven but is based in Boston. The company employs 14 full-time staffers, and enjoys access to about the same number of people at Chen’s lab, as well as additional external consultants.
“Our expectation is probably by the end of next year we could have somewhere between 18 and 20 people. And we’ll grow accordingly,” Humphrey said. “We want to make sure that the balance between internal and external talent is appropriate for our stage of company development.”
Over the coming year, the company plans to fill a variety of R&D, clinical, general and administrative (G&A), positions as well as continue to build its corps of senior executives. That corps includes William LaRochelle, PhD, Chief Scientific Officer; Scott Phillips, Chief Financial Officer; Melinda Merchant Chua, MD, Senior Vice President of Clinical Development; Saul Fink, PhD, Sr. Vice President, Pharmaceutical & Nonclinical Development; and Kristin Robbins, RN, MBA, Executive Director of Program Management & Business Operations.
Humphrey is an adjunct professor at Yale based within the University’s West Haven, CT, campus acquired in 2007 from Bayer, just feet from Chen’s lab. The prospect of returning to the campus, where she worked a quarter century ago, excited Huphrey when Shannon asked her to join Normunity 18 months ago.
“I knew how to build companies. I knew how to bring transformational cancer therapies to the clinic. I’d seen great successes and plenty of opportunities to learn. I said, ‘It’s time. I think I can build my own company.’ Humphrey recalled. “I’ve come back to my starting point with two decades and a half of experience about how to do drug development, and I haven’t looked back,” Humphrey said. “This is really awesome.”