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Neon Therapeutics' Personalized Vaccine Approach Progresses With Combination Immunotherapy Trial


NEW YORK (GenomeWeb) – Cambridge, Massachusetts-based Neon Therapeutics is continuing to make progress in its quest to use predicted neoantigen profiles in tumor samples for developing cancer vaccines and adoptive T cell therapies that can be used alone or in combination with immune checkpoint inhibitors to beat back cancer or prevent its recurrence.

The firm is interested in "exploring the therapeutic potential of targeting neoantigens, not only in vaccinations but also T cell-based strategies," explained Neon Therapeutics Co-founder Catherine Wu, a medical oncology, cancer immunology, and virology researcher affiliated with the Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School.

In general, that is accomplished using a pipeline for sequencing tumor and matched normal exomes, detecting somatic mutations, and using that information to predict the neoantigens that are expected to prompt the most robust immune response so that they can either be incorporated into that individual's personalized cancer vaccine or used to inform the type of T cells that are generated and expanded for the patient.

The company launched in 2015 after securing venture capital funding with the goal of bringing its proposed treatments to as many eligible patients as possible.

"We all saw great value here, great opportunity to deliver something to patients that would potentially be really helpful — and, I think, we've learned more and more over time that it really will be helpful," said Edward Fritsch, Neon Therapeutics' chief technology officer.

Wu, Fritsch, and colleagues from Dana-Farber Cancer Institute and elsewhere used a broadly comparable approach to come up with personalized cancer vaccines that were used to treat half a dozen individuals with melanoma. Those treatment strategies — and patient outcomes over more than two years — were described in Nature last week.

Four of the six melanoma patients who received neoantigen-based vaccination in that study dodged disease recurrence during 25 months of follow up, Wu and her co-authors reported. The other two vaccinated individuals had disease recurrence, but achieved tumor regression after subsequent treatment with the PD-1 targeting antibody drug pembrolizumab.

Neon Therapeutics did not sponsor that study, Wu explained, though she, Fritsch, and other company co-founders such as Nir Hacohen and Eric Lander co-authored the work.

While that study focused on personalized cancer vaccines in the adjuvant setting, Fritsch explained, Neon Therapeutics is now sponsoring a multi-center clinical trial to test its NEO-PV-01 personalized cancer vaccines in combination with the anti-PD-1 checkpoint blockade drug nivolumab (marketed as Opdivo by Bristol-Myers Squibb) in 90 individuals with advanced or metastatic melanoma, non-small cell lung carcinoma, or a form of bladder cancer known as transitional cell carcinoma of the bladder.

That ongoing Phase Ib trial "uses the same formulation and approach that we described and is expanded to three different cancer settings," Wu said. "Patients come to the various centers, but as a centralized entity, the tumors do come to Neon, where they orchestrate the sequencing and analysis and also the manufacture of vaccines."

It is co-sponsored by Bristol-Myers Squibb and is currently recruiting participants at the City of Hope in California, the University of California at Los Angeles Medical Center, Dana-Farber Cancer Center, Washington University, and the MD Anderson Cancer Center.

The company does not yet offer commercial neoantigen-based treatment services, but is starting to partner with researchers and clinicians to test the veracity of neoantigen-based cancer therapies in the hopes of securing US Food and Drug Administration approval of Neon's neoantigen-focused therapeutic approach, Fritsch explained.

In parallel, the team plans to monitor patient responses to the vaccine and anti-PD1 therapy to not only assess the effectiveness of this combination treatment, but also to get a better sense of response predictors, if present.

At the moment, it takes roughly 10 weeks to develop personalized cancer vaccines with Neon's approach, though Fitsch noted that the team is working to bring that down to around four to six weeks.

With the trial, Neon Therapeutics joins the ranks of those pursuing personalized cancer vaccines that complement and boost the veracity of immunotherapy drugs that take the brakes off of checkpoint blockades involving players such as PD-1, PD-L1, or CTLA-4.

High mutational load has been put forward as one proposed indicator of checkpoint blockade response — perhaps because these tumors contain more immune-stimulating neoantigens and anti-tumor response from the start.

By using a personalized vaccine in combination with a checkpoint blockade drug, the team hopes to further boost the levels and effectiveness of T cells that target these neoantigens once the immune checkpoint is removed.

"Our approach is, 'Let's work with checkpoint blockade [immunotherapy] by inducing all these T cells … in conjunction with the checkpoint blockade, get a better immune response against the tumor," Fritsch said. "The biology over the last couple years has really convinced a lot of people that neoantigen T cell responses are going to be the key to fully unlock [immune] checkpoint therapy and maybe even other, conventional therapies," he added.

Another personalized cancer vaccine-focused firm, Germany's BioNTech, hammered out a $310 million deal with Genentech last fall to support its efforts on personalized cancer vaccines developed against neoantigens identified with the IVAC Mutanome approach, for example, in preparation for a phase I trial of BioNTech designed vaccines given in combination with the anti-PD-L1 drug atezolizumab (Genentech's Tecentriq).

Investigators from BioNTech also co-authored a study that came out in Nature last week, concurrent with work from the Wu-led group, that described outcomes in advanced melanoma patients treated with personalized cancer vaccines designed with the help of BioNTech's IVAC Mutanome sequencing approach.

Still other firms such as Gritstone Oncology, Isa Pharmaceuticals, Agenus, Aduro Biotech, and others are taking a crack at cancer immunotherapy applications with a personalized neoantigen component.

More generally, Wu noted that Dana-Farber has other neoantigen-related academic trials that are in the works for individuals with renal cell carcinoma, ovarian cancer, glioblastoma, and other cancer types that are not sponsored by Neon.

"They're basically testing, in these other diseases, whether this theoretically crosscutting approach can be applied in other clinical settings as well," she explained.

Predicted neoantigens tend to be more plentiful in melanoma and other tumor types that are prone to high mutational loads, though Wu noted that investigators hope to find targetable neoantigens in more and more tumor types as related therapies continue to develop.

"Certainly, it's the hope that as we develop refinements in the way that we identify neoantigens th­­­at we can extend this approach to lower mutation rate tumors," she said.