How NextCure is Approaching Women’s Cancers Differently: Perspectives from Three Scientists

Breast cancer. Cervical cancer. Ovarian cancer. Uterine cancer.

Like many cancers that are out there, we’ve made tremendous progress in how we think about and treat women’s cancers. We’re able to use techniques such as RNAseq, whole genome sequencing, and epigenomics to get a better understanding of key differences between our normal cells and tumor cells that have gone rogue. We can offer women different treatment options besides just chemotherapy and radiation, with other potential therapies such as CAR T continuously being studied.

We still have a ways to go, though, because if there’s anything we’ve learned through all these powerful tools, it’s that treating cancer is a constant race between us and the disease.

Scientists and drug developers around the world, including in the BioHealth Capital Region, are working tirelessly to uncover new leads. NextCure, located in Beltsville, Maryland a few miles up the road from the University of Maryland, is armed with not only a sophisticated drug discovery platform, but a savvy team of intuitive scientists that can connect the dots in the data to create innovative therapies.

BioBuzz talked to three scientists from the NextCure team to get more perspective into what makes cancers, particularly women’s cancers, tricky to target, and what NextCure is doing to keep pace in the race.

Dr. Priyanka Kothari started at NextCure in 2020 after finishing her graduate training and has quickly moved up the ranks to a Scientist III position, working on the discovery side of the drug development process to better understand potential hits uncovered by the company’s FIND-IO platform. She is an expert in utilizing an array of assays to understand the mechanics of how cells interact with each other and their environments. She received her PhD from Johns Hopkins School of Medicine in 2020.

Dr. Alina Barbu, who also joined NextCure in 2020 and is currently Associate Director of Biomarkers, is a seasoned immunologist with more than 10 years of experience in understanding immunologic signal transduction pathways and how different immune cells work. She received her PhD in 2007 from the Weizmann Institute of Science and did two postdoctoral fellowships at the NIH as well as Washington University. In addition to her biomarker work at NextCure, she also continues to volunteer at the NIH as a researcher.

Dr. Shannon Kahan joined in 2021 as a Scientist focused on immunology/oncology. She received her PhD at Louisiana State University School of Medicine. In addition to doing her postdoctoral work at the University of Alabama at Birmingham, she was also awarded a prestigious American Cancer Society fellowship. She works at the intersection between the biomarker and clinical teams to better understand potential drugs of interest and their biology to see whether they’d be good candidates for a clinical trial.

Thinking beyond the genes

When looking at checkpoint inhibitor targets, PD-1, PD-L1, and CTLA-4 continue to reign supreme in FDA-approved therapies. While we do see checkpoint inhibitors being used to treat some types of women’s cancers, as a whole they’re still mostly used to treat carcinomas and lung cancer.

We need new checkpoint inhibitor targets and strategies.

With an arsenal of high-throughput sequencing assays at our disposal, it’s very tempting for scientists to sequence tumors, compare to normal cells, and use that data to inform potential targets. While it sounds promising on paper, there are a few issues:

  1. DNA mutations and RNA expression are just one part of the story – just because a gene is up-or-down regulated, for example, does not mean it gets expressed into protein, or that it plays a role in cellular dysfunction.
  2. How well a therapy works is not just dictated by tumor expression profile – if T cells are exhausted, for example, it doesn’t matter if the target is highly expressed in 99% of cells.
  3. Similarly, the more we learn about the tumor environment, the better we understand how it determines the success of a therapeutic approach.
  4. No two tumors are exactly alike, even if they’re the same type of cancer.

“Think of it like a snowstorm – from your window it all looks white and fluffy, but when you zoom in you see that each snowflake is different. It’s the same with cancer – we group diseases into ‘breast cancer’ or ‘lung cancer’, but the profiles can be completely different between two people,” said Barbu. She added, “Breast cancer is a great example – you could be HER2+, ER+, or PR+, or you could be triple negative. And within all those subtypes you have different levels of receptor expression and different tumor microenvironments that dictate how well a treatment will work.”

Trying to uncover all the nuances in women’s cancers to figure out a new treatment can be overwhelming – where do you even start, and what constitutes “enough data”? While we certainly can’t investigate every aspect of tumor biology, NextCure’s FIND-IO platform can uncover more meaningful leads than just sequencing alone.

“Instead of just looking at gene expression, we’re focused on phenotypic changes in the cells. If we overexpress certain molecules in the tumor cell, for example, what effect does that have on how the tumor cell interacts with T cells? Does it impact cell differentiation or proliferation? Cytotoxicity? Cytokine release profiles?” said Kothari.

And rather than start with a particular cancer type in mind, scientists let the platform inform the indications. After uncovering hits, the team assesses expression levels in various cancer types to inform preclinical strategy.

“Though there are a lot of parameters that we evaluate, the FIND-IO platform is very high-throughput and modular, meaning we can change the assay to specifically answer the question at hand,” Kothari added.

Monotherapy or Combination Therapy – that is the question.

Or at least one of the questions, that is.

When figuring out the best clinical strategy for a new target, scientists will inevitably come to a crossroad – should we do a trial where we test our drug by itself, or should we combine it with an existing therapy, such as chemotherapy or an approved checkpoint inhibitor such as pembrolizumab?

The answer is anything but straightforward.

For example, with a monotherapy trial you don’t have to go through as many hoops to get permission from another company to use their drug, which would otherwise add time that patients might not have. There’s also nothing stopping a company from trying both a monotherapy arm and a combination arm, but the trial will be more expensive and would require more patients to enroll, which can be a potential hurdle.

Another consideration is that you can’t just throw two drugs together for the sport of it – it’s the difference between throwing random ingredients together that you think would be nice in a dish vs. being a Michelin star chef who knows the ins-and-outs of how everything marries together and complements each other to bring out the best flavor.

In cancer drug development it’s similarly not about a binary “low” vs “high” when thinking about whether an investigational therapy may work – you need to evaluate the general percentage of target expression in that tumor. You need to consider the environment surrounding the tumor and how immune cells are interacting, otherwise you’re missing key details that could completely derail your efforts.

Let’s, for example, look at two of NextCure’s programs – NC410 and NC762.

NC410 is a decoy protein that prevents an immune checkpoint receptor called LAIR-1 from engaging its collagen-containing ligands both within and outside of the tumor environment.  LA

IR-1 is expressed in many immune cell types and its collagen-mediated activation results in exhaustion of immune cells with anti-tumor potential, such as CD8+ T cells, for example.  “Many tumors, including some women’s cancers, have high collagen expression in their surrounding environment. Not only can NC410 take care of the collagen-mediated immunosuppression, but it can target elements of the extracellular matrix, potentially remodeling the physical barrier surrounding the tumor ,” said Barbu.

NextCure scientists saw a golden opportunity for a synergistic combination between NC410 and a PD-1 blockade, since it has  been shown that high levels of collagen are correlated with resistance to PD-1 checkpoint therapies and thus also associated with poor cancer prognoses. NextCure currently has a Phase 1b/2 study ongoing evaluating the combination of NC410 and pembrolizumab in several types of high-collagen cancers, including endometrial and ovarian cancers.

Think of the collagen in a tumor like a wall – NC410 acts as the cannon that can blow open a hole in the wall, which makes it much easier for immune cells to move through and attack. The combination therapy can also further restore the functionality of the invading immune cells. “For NC410 it isn’t just about a new target, but how can you use this therapy to help get functional T-cells into the tumor when PD-1 blockade alone falls short,” Kahan noted.

NC762, on the other hand, is an antibody that binds to a transmembrane protein called B7-H4. B7-H4 is not commonly expressed in normal tissues, but heavily expressed in many cancers, including breast and ovarian. NC762 works through several mechanisms, including killing B7-H4 positive tumor cells via antibody-dependent cellular cytotoxicity. In this instance, it makes more sense to evaluate NC762 as a monotherapy, without combining it with a checkpoint blockade, since the target is more tumor-specific. Currently NC762 is in a Phase 1 trial in several B7-H4 expressing cancers, including breast and ovarian.

Another important consideration in the monotherapy vs. combination discussion is time.

Kahan knows this first hand, with one of her postdoc mentors having worked with Dr. Rafi Admed, whose work on PD-1 helped to pave the foundation for the PD-1 checkpoint inhibitors we have today. “The targeting of PD-1 on exhausted T cells during viral infection in mice was first described in 2005, and it took many years from it to go from basic science in mice to being a prominent treatment for cancer in humans. Time is something we always have to think about when figuring out the clinical path for these new targets. In industry you’re doing all of this on patients’ time, and while we’d ideally like to have a monotherapy that works beautifully on its own, that’s just not the reality for a lot of cancers.”

Keeping patients top of mind

While the NextCure team works tirelessly to advance their pipeline, they also make sure to take a step back and remember what all of this is for.

“Something we always have to remember is that these people are traveling, sometimes extremely far distances, to try our treatments, not knowing if they’re actually going to work for them,” said Barbu. “It’s not only on the patients’ mind that they’re in a clinical trial, but it’s also on the minds of their families and friends. It’s not just about NextCure’s success as a business, but giving these individuals the best chance for success.”

And while clinical trial failures are hard to accept, we must realize that not all is lost. While that target might not be great for a potential new cancer treatment,, it could still potentially serve as a biomarker that can help detect disease earlier. While that’s not the slam dunk we hope for, it still absolutely could be a win.

A long road ahead, but making progress

While the NextCure team continues to make strides, there are some factors that are still out of their control, particularly in women’s cancers.

“Something I think we sometimes forget about is women’s cancers are so hard to treat not just because of their expression profiles or tumor microenvironment, but because often women don’t get properly diagnosed until the cancer has advanced and metastasized,” noted Kahan. “For example ovarian cancer is often dismissed for other diseases such as endometriosis.”

A contributing factor to late detection is also, unfortunately, due to psychological and sociological factors. Women, especially those with families, often focus on nurturing others while neglecting their own needs. Further, it’s no secret that women, especially women of color, are sometimes gaslit by their physicians and do not have their pain taken seriously.

Treatment costs are also a major barrier – Kahan, whose mother had cancer, knows this personally. “Her antibody treatments were $8,000 a month, and we didn’t know whether or not they were really going to work for her.” There are, though, new sequencing and functional tools on the horizon that could lessen this burden and increase the likelihood of success.

“Liquid biopsies, for example, are becoming more sensitive, and I think in 10-15 years we’ll see a major shift to liquid biopsies vs. the more traditional, invasive biopsy.”

And while intense sequencing and functional assays are sometimes saved for clinical research, Kahan, Barbu, and Kothari think that a future where these analyses become standard practice is not that far off.

“While all these tests may seem expensive right now, I think that we’ll see the cost continue to drop with time, much like what we’ve seen with DNA sequencing,” said Kahan. “You also have to think about it in perspective – you might have to pay a few thousand up front for a liquid biopsy and other kinds of tests such as sequencing and IHC, but if it’s able to better inform which treatments could work for you, it will save you money in the long run because you aren’t paying thousands a month for an antibody therapy that might or might not work. It will likely save money and effort to do more analysis up front rather than throwing something to the wind and hoping it works.”

And with that, the work continues.