NEW YORK – A recently closed $72 million financing round will bolster Swiss biotech Nouscom's efforts to test the efficacy of its two lead cancer vaccines not only in treating late-stage refractory cancers but also in preventing cancer in high-risk individuals.
Nouscom is far from the only biotech trying to treat cancer using a viral vector to induce immune responses. Companies like Moderna and BioNTech, for example, have made headway with personalized neoantigen cancer vaccines for melanoma and other advanced tumors. Nouscom believes its vaccine candidates could have a leg up on competitors, however.
Nouscom's two lead candidates, an off-the-shelf vaccine dubbed NOUS-209 and a bespoke version dubbed NOUS-PEV, are built with nonhuman viral vectors. The off-the-shelf vaccine targets 209 preselected neoantigens, and the personalized version is engineered to target 60 neoantigens unique to each patient's tumor. According to Nouscom CEO Marina Udier, the number of neoantigens these therapies target could be an advantage.
"We can encode large payloads into these vectors, which we believe is advantageous since cancers are heterogenous and prediction algorithms are not perfect," Udier said. "This really gives the immune system the best chance to have a powerful response."
Toward a Lynch syndrome vaccine
For the off-the-shelf vaccine, NOUS-209, Nouscom designed it to target neoantigens that specifically show up in cancers that are DNA mismatch repair deficient (dMMR) or have high microsatellite instability (MSI-high). And since Lynch syndrome, an inherited condition that increases the risk of colorectal and other malignancies, is caused by these biomarker deficiencies, the firm believes it could potentially grab a foothold in this setting where few treatment approaches have been successful.
People with Lynch syndrome who've inherited DNA mismatch repair genes have up to an 80 percent chance of developing cancer. And while frequent and aggressive screenings may identify cancers early in Lynch syndrome patients, Udier emphasized that there aren't any effective therapeutic approaches to prevent cancer from developing in the first place.
To this end, Nouscom, in collaboration with the National Cancer Institute, is conducting a Phase I trial of NOUS-209 in 45 participants with Lynch syndrome. To partake in the study, patients must have a germline pathogenic or likely pathogenic mutation in an MMR gene. If negative for such a mutation, the patient must have a personal history of a non-sporadic premalignant lesion associated with Lynch syndrome, like colon polyps, or a non-sporadic MMR-deficient malignant tumor. However, patients in the trial cannot have evidence of invasive cancer for at least six months before screening.
According to Udier, the trial has already produced "quite compelling" preliminary data. In the first 10 participants, the vaccine was safe, well tolerated, and induced broad immunogenic T-cell responses.
Udier credits the vaccine's safety profile to the tumor-specific frameshift peptides that Nouscom selected for NOUS-209. Indeed, the vaccine's safety profile, according to Nouscom, is part of the reason the firm has permission from the US Food and Drug Administration to test it in a population of people who don't have an active cancer diagnosis.
The peptides don't resemble protein sequences found in the normal human proteome, which means they're specific to cancer tumors, Udier emphasized. Not every tumor has all 209 neoantigens, but many of them are shared across dMMR and MSI-high tumor types, which in turn, led Nouscom and NCI to recognize the treatment's potential in a heterogenous condition like Lynch syndrome.
Udier is optimistic that if the Phase I Lynch syndrome trial continues like it has been, it's going to be "overwhelmingly positive." Nouscom is discussing with its collaborators and other experts in the scientific community about how to move the clinical program forward for NOUS-209 in this setting.
Designing a randomized trial for preventing cancer in those who don't have it can be tricky, Udier acknowledged. The burden of safety in a trial involving otherwise healthy individuals is higher, and finding a comparator is challenging. While Nouscom has made progress on designing a randomized trial protocol, Udier said the firm hasn't publicly disclosed its design but hopes to solidify the plan in 2024. In the meantime, Nouscom is focused on publishing a full set of data from the Phase I trial with the NCI in coming months.
Beyond Lynch syndrome, Nouscom is also evaluating NOUS-209 with Merck's immune checkpoint inhibitor Keytruda (pembrolizumab) in a Phase II randomized trial for patients with advanced dMMR or MSI-high colorectal cancer. The firm is also expecting a readout from that trial next year.
Personalized program takes shape
Nouscom has also been making headway on its personalized vaccine program, NOUS-PEV, and zeroing in on cancer indications with high unmet need for the next phase of development. The firm has been testing NOUS-PEV with Keytruda in a Phase I trial involving patients with advanced melanoma and PD-L1-expressing non-small cell lung cancer.
"We are planning to kick-start the personalized [vaccine] program in Phase II indications," Udier said, adding that the $72 million the company recently raised within a Series C financing round will allow it to scale up accordingly.
Udier acknowledged that other biotech companies have later-stage personalized cancer vaccines in the clinic for advanced melanoma. Moderna, for instance, has reported encouraging efficacy for its mRNA cancer vaccine, V940, plus Keytruda when given in the adjuvant setting to high-risk melanoma patients.
Nouscom hasn't announced any plans to pursue the same indication with NOUS-PEV, but if the firm were to do so, Udier believes that NOUS-PEV's ability to target 60 neoantigens unique to each patient could be a potential advantage. Moderna's vaccine goes after 34 neoantigens unique to the patient, and BioNTech's vaccine goes after 20 neoantigens.
"We are two to three times over that, and we think that is advantageous because we have more opportunities, more shots on goal, to actually hit the immunogenic antigens," she said. "And we induce high-quality CD8 and CD4 T cells that are of memory phenotype and infiltrate tumors when the tumor is present and proliferate and expand in that tumor. … We have not seen either mRNA company show data that is that compelling."
NOUS-PEV's viral vector technology, Udier said, could induce "better immune responses in more patients."
Of course, Nouscom has to date only tested its personalized vaccine in a Phase I study and a small Phase II pancreatic cancer study, so additional trials will be needed to prove the advantages Udier described. Additionally, as of now, the process of resecting a patient's tumor, developing the NOUS-PEV vaccine, and administering it as a treatment takes about eight weeks, which could be a challenge for patients with advanced disease.
"There is an opportunity to bring that time down a bit," Udier acknowledged. "We're working on that for the next stage of development."