NEW YORK – Elicio Therapeutics is advancing a mutant KRAS (mKRAS)-targeted cancer vaccine toward the pivotal trial stage, using a technology that not only shows the potential to successfully and safely target an until recently undruggable protein but opens a new avenue to repositioning drugs that have been too toxic to administer to humans in the past.
Boston-based Elicio, along with numerous academic partners and Natera, whose Signatera platform was used to assay patient circulating tumor DNA (ctDNA) throughout the trial, recently published the results of the Phase I AMPLIFY-201 trial in Nature Medicine. They demonstrated that the ELI-002 2P vaccine was safe and well tolerated, and that it resulted in a measurable biomarker response among 20 participants with pancreatic cancer and five with colorectal cancer (CRC).
"We chose to study a target that is really relevant for many patients because it's present in one-quarter of all cancers out there," said Chris Haqq, executive VP and head of research and development at Elicio.
Haqq said that one of the reasons KRAS makes an attractive target is that mutations in this gene typically occur very early in tumor development and don't get lost as the tumor evolves.
"That's an ideal situation for a therapeutic," he said, explaining that this leads tumors to become "addicted" to KRAS mutations, making it potentially less likely to develop therapy resistance.
"It has been very difficult to target in the past," Haqq said, "because KRAS mutations occur inside the cell, where an antibody wouldn't be able to make an attack."
To get around this, Elicio is developing a technology that trains the body's T cells to detect these mutations and attack affected cells.
"We're taking a formerly undruggable target," Haqq said, "and now we've got a way, through the powerhouse of the lymph node, to make T cells in the patients that are capable of specifically recognizing the tumor cells with those mutations and then eliminating them."
The challenge of targeting KRAS and its central role in many tumors has led to a robust field of researchers and pharmaceutical companies trying to do just that. In 2021, for example, the US Food and Drug Administration approved Amgen's Lumakras (sotorasib) for previously treated, locally advanced, or metastatic non-small cell lung cancer patients harboring the KRAS G12C mutation; and Mirati Therapeutics' Krazati (adagrasib) has been approved in the US, Europe, and the UK.
ELI-002 consists of amphiphile (amph)-modified long peptides corresponding to known KRAS mutations, as well as an amph-modified TLR9-agonistic CpG-7909 DNA. CpG-7909 is a short synthetic single-stranded DNA molecule containing unmethylated CpG dinucleotides that mimic microbial DNA, stimulating the TLR9 receptor.
The CpG-7909 adjuvant facilitates delivery of ELI-002 to the lymph nodes, making it key to the vaccine's success. The peptide antigens and CpG-7909 are conjugated to albumin-binding lipids, which targets them to the lymph nodes. In the case of CpG-7909, this also avoids the toxic effects often associated with that synthetic DNA molecule.
Past studies involving CpG-7909 had shown the frequent occurrence of inflammatory reactions, including potentially deadly cytokine storms.
Haqq said that CpG-7909 is completely metabolized within the lymph node, where the same lipid structure used to target delivery to the lymph node also facilitates vaccine uptake into antigen-presenting dendritic cells.
"The biodistribution into the lymph node is what's making the efficacy better [and] also the safety," Haqq said. "We can anticipate that the same targeting method to take things into the lymph node could now be used to better reposition other drugs that we know have a strong immune effect but that were too toxic to administer to humans."
Few treatment-related adverse effects were seen in the AMPLIFY-201 trial, and those that were, were mild, consisting of fatigue, injection site reaction, and myalgia. One serious event did occur –– a grade three abdominal wall hematoma –– but was determined to have been related to a biopsy performed to confirm progression, rather than to the vaccine itself.
Also important to the success of the AMPLIFY-201 trial, Elicio enrolled patients who not only had KRAS mutations, but who were negative for the overt presence of disease by imaging studies and who showed evidence of minimal residual disease (MRD) by the presence of ctDNA.
"[This], to my knowledge, is the first time somebody has done a dose-escalation, Phase I study in a ctDNA- or biomarker-enriched patient population," said Alexey Aleshin, chief medical officer and general manager of oncology at Natera.
Aleshin explained that one of the challenges in conducting cancer vaccine trials has been parsing the vaccine's effect from that of other treatments given. Using ctDNA clearance as a secondary trial endpoint addressed this, he said, by enabling Elicio to avoid enrolling late-stage, metastatic cases, which allowed the company to administer the vaccine without accompanying immunotherapies or other treatments.
The FDA issued new guidance on the use of ctDNA in clinical trials in mid-2022, and cancer trials are beginning to explore the clinical utility of ctDNA dynamics as early therapy response endpoints. Johns Hopkins University and the Canadian Cancer Trials Group, for example, published the results of a study last year, also in Nature Medicine, that showed reliable correlations between ctDNA levels and radiographic response to treatment.
"If we can actually show that some of these patients have a ctDNA decrease or clearance," Aleshin said, "that would be a really strong sign that the drug works even though in the adjuvant setting there's really nothing to monitor. These patients, by definition, have no radiological evidence of disease. I think that was the super innovative component of the study."
Further bolstering calls for the use of ctDNA in oncology settings, the US National Comprehensive Cancer Network on Monday issued guidelines supporting ctDNA as an emerging post-surgical prognostic biomarker in the CRC setting, although the organization stopped short of recommending its use in multigene assays to inform either recurrence risk or adjuvant treatment.
The ELI-002 formulation tested in the AMPLIFY-201 trial –– ELI-002 2P –– contained peptides for two of the most common KRAS mutations, G12D and G12R. Haqq said that in future studies, Elicio will field a seven-peptide formulation, targeting a wider range of mutations.
"The reason that we started with the two [peptides] was an accident of the pandemic," Haqq said. "All the production was ramping up in 2020, right when all the vaccine manufacturers in the US had to devote their attention to making vaccines for COVID."
Mariano Alvarez, CSO of precision oncology company DarwinHealth, called the AMPLIFY-201 study results "very promising," while noting that the study was not without certain limitations.
"While the vaccine is composed [of] a mixture of peptides providing 9-mer and 10-mer for HLA-I and longer peptides for HLA-II, the efficiency of HLA-I presentation by the tumor cells is not evaluated," he said.
Nonetheless, Alvarez said that it was encouraging that 21 of 25 participants showed ex vivo T-cell-mediated responses.
"However, biomarker clearance was observed in only six patients," he said, "suggesting that activation of a specific T-cell response might not be accompanied by clearance of the tumor cells."
This, he explained, could be due to insufficient HLA-I presentation of the mKRAS antigens in the tumor cells and/or the presence of an immunosuppressive tumor microenvironment causing T-cell exhaustion.
Haqq said that patient recovery from prior chemotherapy provided a hint as to why some patients didn't show particularly strong T-cell responses.
"The one thing that correlated with not making a good response to the vaccine was having very low lymphocyte counts at the beginning, and that's from chemotherapy," he said.
Elicio has now launched a Phase II trial, and Haqq said that entry criteria was modified based on the chemotherapy recovery finding, so that patients must have normal lymphocyte levels prior to vaccination. The company aims to recruit up to 135 participants this year and to announce the first analysis of the study's data in the first quarter of 2025.
Haqq also expects to see longer vaccine response times in the Phase II trial, because of the seven-peptide vaccine formulation.
"By including from the beginning, a larger number of mutations," he said, "we hope to not only cover what's initially present in the patient but prevent any resistance mechanisms from occurring in the cancer."
Haqq commented that Elicio hopes that the AMPLIFY-201 trials, and those following it, sets a precedent with the FDA for being able to treat patients and to use ctDNA as a marker of disease during these early periods, where there would normally just be observation.
"Prior adjuvant studies have to wait multiple years and in randomized setting to [observe] relapse-free survival using radiographs," Haqq said. "But because we chose the patients for the initial study to all have elevated tumor markers, we realized we could use those markers to see the initial activity. And that was really helpful in looking to find the right dose to recommend for the Phase II."
Haqq said that he expects this trial design to facilitate "a lot" of drug discovery in the adjuvant setting.
"I think [this trial] is a testament to where the field is headed," added Aleshin.