Novel immune checkpoint inhibitor was safe and immunogenic in patients with solid tumors
The VISTA-blocking MAb KVA12123 (Kineta) was well tolerated and induced robust T-cell responses and proinflammatory markers in 18 subjects with advanced solid cancers. The dose-escalation Phase 1/2 VISTA-101 trial tested KVA12123 as a monotherapy and in combination with the PD-1 inhibitor pembrolizumab (Keytruda, Merck).
VISTA, which is a novel immune checkpoint that inhibits T-cell activation, is overexpressed in tumor-infiltrating lymphocytes.
Immune checkpoint inhibitor combinations in clinical development on multiple fronts
The PD-L1 inhibitor atezolizumab (Tecentriq, Roche) in combination with chemotherapy reduced the risk of progression or death by 35% compared to standard-of-care hormonal therapy in 400 patients with metastatic castration-resistant prostate cancer. The Phase 3 CONTACT-02 trial also reported median progression-free survival of 6.3 and 4.2 months in the experimental and control cohorts, respectively.
Seventy-nine percent reduction in death or disease, compared to chemotherapy, was observed following first-line treatment with the combination of anti-PD-1 nivolumab (Opdivo) and anti-CTLA-4 ipilimumab (Yervoy, both BMS) in subjects with metastatic colorectal cancer enrolled in the Phase 3 CheckMate-8HW trial. The combination is widely used in treatment of melanoma.
A combination of pembrolizumab with a masked anti-CTLA-4 “safebody” ADG126 (Adagene) was safe and induced 100% disease-control rate in 12 patients with metastatic microsatellite-stable colorectal cancer in a Phase 1/2 trial. Two partial responses persisting for >55 weeks were reported. ADG126 is masked with a peptide, which is designed to be cleaved specifically in the tumor microenvironment, thus increasing the safety of the treatment.
Finally, the PD-L1-specific MAb avelumab (Bavencio, Merck KGaA) with the oral probiotic GEN-001 as a third-line treatment induced a 17% response rate in 42 subjects with PD-L1-positive advanced gastric cancer or gastroesophageal junction adenoma. GEN-001 contains a single strain of the commensal bacterium Lactococcus lactis, which has been shown to activate antitumor T cells.
Two approvals for PD-1 pathway inhibitors
The US Food and Drug Administration has approved pembrolizumab plus chemoradiotherapy for stage III-IV cervical cancer. The decision builds on Phase 3 trial results showing that the regimen reduced the risk of disease progression by 40% compared to placebo.
The European Commission has approved subcutaneous administration of atezolizumab for several solid cancers. Compared to the standard intravenous route, such injection is less invasive and saves 80% of treatment time.
New shingles vaccine induced 100% response rate in a mid-stage clinical trial
The adjuvanted subunit varicella zoster virus vaccine CRV-101 (amezosvatein, Curevo) demonstrated safety and non-inferior immunogenicity, compared to the marketed vaccine Shingrix (GSK) in >850 adults aged ≥50 y. The Phase 2 trial reported 100% seroconversion one month after the 2-dose regimen had been completed.
CRV-101 consists of the viral glycoprotein E and an adjuvant targeting the TLR4 pathway for enhanced immunogenicity.
KRAS vaccine was safe and immunogenic in early trial with solid cancers
Eighty-four percent response rate following administration of the KRAS vaccine ELI-002 (Elicio) was reported from the Phase 1 AMPLIFY-201 trial involving 25 subjects with colorectal or pancreatic cancer.Citation1 The treatment was safe and induced both CD4+ and CD8+ T cell responses.
ELI-002 is a CpG-adjuvanted off-the-shelf vaccine targeting mutated KRAS protein, which is one of the most common tumor-associated neoantigens.
Reference
- Pant S, Wainberg ZA, Weekes CD, Furqan M, Kasi PM, Devoe CE, Leal AD, Chung V, Basturk O, VanWyk H, et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat Med. 2024. doi: 10.1038/s41591-023-02760-3.