SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.
The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.
The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors.
Checkpoint inhibitors have revolutionized cancer treatment. They are however not as effective in patients with “cold tumors” (MSS), as these tumors effectively hide themselves from the immune system and do not trigger an immune response following treatment with checkpoint inhibitors.
GRANITE is a personalized neoantigen immunotherapy designed to trigger a strong T-cell immune response against a patient’s tumor. A biopsy of the tumor is performed to identify unique mutations (neoantigens) present in the tumor of patients. An AI platform, EDGE, developed and designed by Gritstone Bio is able to identify critical T-cell vaccine targets, and predict which neoantigens are most likely to be recognized by the immune system of patients. The system has an 80% accuracy rate in selecting the top 20 most immunogenic neoantigens, most likely to generate an immune response in a given patient. The selected neoantigens are incorporated into a chimpanzee adenovirus-based primer vaccine and a Self-Amplifying mRNA (SAM) booster vaccine to train the immune system that leads to an induction of both cytotoxic T-lymphocyte and memory T-cell dependent immune responses, that specifically target and destroy the patients cancer cells that express these neoantigens. This vaccine (GRANITE) is administered via intramuscular injection alongside immune checkpoint inhibitors. Thus GRANITE primes the immune system to recognize and attack these tumors. This vaccine is customized for each patient based on the unique mutations of their tumor. In essence, GRANITE helps make the “cold tumors” visible to the immune system, potentially improving patient outcomes.
GRANITE immunotherapy regimen was evaluated in combination with Nivolumab and Ipilimumab, and compared to the combination of Nivolumab and Ipilimumab alone in a Phase1/2 involving patients with advanced metastatic solid tumors. This study demonstrated robust T-cell activation against targeted neoantigens with no dose-limiting toxicities, and over 50% of patients had a reduction in their circulating tumor DNA (ctDNA) and improved Overall Survival (Palmer CD, et al. Nature 2022).
GRANITE immunotherapy regimen is now being studied as first line metastatic treatment in a randomized Phase 2 trial, among patients with Microsatellite-Stable (MSS) Colorectal cancer patients. GO-010 is an ongoing Phase 2/3, randomized, open-label, multi-center study evaluating the efficacy and safety of GRANITE immunotherapy regimen in combination with Checkpoint Inhibitors (CPIs) as an add-on to Fluoropyrimidine/Bevacizumab as maintenance treatment, following first line therapy with FOLFOX/Bevacizumab, in patients with mCRC. In this study, 104 patients were randomized in a 1:1 ratio, and 67 patients were included in this treated analysis with 39 patients assigned to the GRANITE arm and 28 patients to the control arm. (36 patients withdrew from the study primarily due to early progressive disease or withdrawal of consent, and one patient has yet to begin study treatment). The vaccine manufacturing success rate was 100%. Both treatment groups were well balanced with regards to demographics, clinical characteristics stage, sidedness and presence of liver metastases. Approximately 75% of patients had liver metastases. For the Phase 2 portion of this study, the Primary end point being assessed is molecular response defined as 30% or more decrease from baseline in ctDNA. For the Phase 3 portion of this trial, the Primary end point is Progression Free Survival (PFS). Secondary end points for both Phase 2 and 3 include Adverse Events, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DoR) and Clinical Benefit Rate.
Preliminary data from the Phase 2 portion of a Phase 2/3 study showed a positive early trend in PFS for GRANITE immunotherapy patients with a Hazard Ratio (HR) of 0.82 in all patients, HR of 0.52 in high-risk patients1 (more than 90% with liver metastases). The median PFS was 12 months with GRANITE immunotherapy versus 7 months for the control group. Long-term ctDNA responses aligned with positive PFS trend favoring GRANITE immunotherapy patients versus control patients.
In the high-risk group, between first blood draw (time of randomization) and last blood draw (most recent study visit), the ctDNA shifted from high (more than 2% VAF-Variant Allele Frequency) to low (2% or less VAF) in 56% of patients treated with GRANITE immunotherapy versus 22% of control patients. Progressive disease was observed in 44% versus 78% respectively, within this group.
In the low-risk group of patients whose ctDNA was negative after induction chemotherapy, sustained ctDNA negativity was observed in 67% of GRANITE immunotherapy recipients versus 38% in the control patients. Progressive disease was observed in 11% and 38% of these patients, respectively. GRANITE immunotherapy was well tolerated and vast majority of adverse events were Grade1/2 and no patients discontinued study treatment due to an adverse event.
In conclusion, this preliminary Phase 2 results are highly encouraging and suggested that GRANITE immunotherapy demonstrated positive early PFS and long-term ctDNA responses, compared with Fluoropyrimidine/Bevacizumab alone, in front-line metastatic MSS-Colorectal cancer, providing the rationale for a confirmatory Phase 3 trial.
A randomized phase 2 study of an individualized neoantigen-targeting immunotherapy in patients with newly diagnosed metastatic microsatellite stable colorectal cancer (MSS-CRC). Hecht JR, Spira AI, Nguyen AV, et al. J Clin Oncol 43, 2025 (suppl 4; abstr LBA13). DOI 10.1200/JCO.2025.43.4_suppl.LBA13
