Bispecific immunotherapy improves long-term survival in metastatic melanoma
First-line treatment with the bi-specific T-cell receptor tebentafusp (Immunocore) induced 3-year overall survival of 27% in HLA-A *02:01-positive patients with metastatic uveal melanoma, compared to 18% in a control group receiving standard-of-care immunotherapy or chemotherapy. The Phase 3 KIMMTRAK trial also reported median overall survival of 22 and 17 months, respectively.Citation1
Tebentafusp is an engineered T-cell receptor targeting the gp100 antigen overexpressed in melanoma and the CD3 T-cell co-receptor. It is thus designed to engage both CD8+ and CD4+ T cells with the malignant cells.
Malaria vaccine reduces childhood mortality
The only approved malaria vaccine RTS,S/AS01 (Mosquirix, GSK) decreased the risk of death by 13% and of severe disease by 22% in children from Ghana, Kenya, and Malawi where the vaccine has been distributed in a pilot program in the past 4 years.Citation2 RTS,S/AS01 is administered in three doses to children under age five.
The World Health Organization also recommended a second malaria vaccine, R21/Matrix-M, which showed a 75% efficacy against clinical malaria in 4,800 children enrolled into a Phase 3 trial.Citation3 This efficacy is similar to that observed in previous trials for RTS,S/AS01.
Malaria accounts for approximately half a million annual childhood deaths in sub-Saharan Africa alone.
Oncolytic virotherapies show promise in two cancer types
The oncolytic adenovirus VCN-01 (Theriva Biologics) combined with the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) induced intratumoral CD8+ T cells and overall survival of 10–15 months in subjects with recurrent or metastatic squamous cell carcinoma of the head and neck enrolled into a Phase 1 trial. VCN-01 is designed to replicate in tumor cells and turn them immunologically hot by destroying the surrounding stromal tissue.
The herpes simplex virus-based CAN-3110 (Candel Therapeutics) was well tolerated and increased intratumoral CD4+ and CD8+ T cells in a Phase 1 trial with 41 recurrent glioblastoma patients.Citation4 Importantly, HSV seropositivity was correlated with extended survival. CAN3110, which is administered by a single intratumoral injection, has its virulence genes controlled by the nestin promoter, which is active specifically in glioblastoma cells.
mRNA vaccines recognized by a Nobel Prize continue to expand
The 2023 Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for their contributions to the development of mRNA vaccines. These vaccines have been deployed throughout the world in the response to the COVID-19 pandemic.
Meanwhile, a combination of mRNA vaccine for SARS-CoV-2 and influenza virus (BioNTech & Pfizer) was safe and immunogenic in healthy adults <65 years of age enrolled in a Phase 1/2 trial. The vaccine, which previously received the US Food and Drug Administration (FDA)’s Fast Track designation, is a variant of the most widely used COVID-19 vaccine, BNT162.
Another Phase 1/2 trial reported safety and antigen-specific T-cell responses induced by the self-replicating mRNA SARS-CoV-2 vaccine EXG-5003 (Elixirgen Therapeutics), administered as a prime 2 months before vaccination with one of the approved mRNA vaccines, BNT162b2 or mRNA-1273 (Moderna).Citation5 The two-dose intradermal lipid-free vaccine expresses the receptor-binding domain of the viral spike protein in a temperature-dependent manner: active at 33°C typical for skin, but inactive at 37°C to prevent systemic reactions.
Telomerase vaccine improves condition of mesothelioma and melanoma patients
The telomerase vaccine UV1 (Ultimovacs) together with the PD-1 and CTLA-4 inhibitors nivolumab and ipilimumab (both BMS) doubled the objective response rate to 31%, compared to treatment with the checkpoint inhibitors alone, in malignant mesothelioma. The randomized, open-label Phase 2 trial reported median survival of 15 and 11 months, respectively.
Based on these results, the FDA has granted UV1 its Orphan Drug designation in mesothelioma.
UV1 also provided long-term benefits to patients with advanced non-resectable or metastatic melanoma. Of 16 patients who received UV1 with the PD-1 inhibitor pembrolizumab (Keytruda, Merck), 11 were alive at the 4-year mark, and no treated patient died during the last year.
UV1 elicits T-cell responses against human telomerase, which is essential for survival of cancer cells and is therefore overexpressed in ~90% of all cancers.
Tree-pollen allergy immunotherapy improves condition in children
Sublingual immunotherapy (ALK) for allergic rhinoconjunctivitis caused by tree pollen improved symptoms score by 22%, compared to placebo, in almost 1,000 children aged 5 to 17. The randomized, placebo-controlled Phase 3 trial took place during an entire birch-pollen season.
The immunotherapy tablet is approved in EU (ITULAZAX) and Canada (ITULATEK) for treatment of adults ≤65 years old.
Therapeutic vaccine improves treatment with immune checkpoint inhibitors in head-and-neck cancer
The subcutaneous HPV vaccine PDS0101 (PDS Biotech) combined with pembrolizumab led to a 2-year survival of 74% in the Phase 3 VERSATILE-002 trial with HPV16-positive head-and-neck cancer patients. The typical 2-year survival rate in this population is <30% for immune checkpoint inhibitors alone.
PDS0101, which received FDA’s Fast Track designation, is designed to induce cell-mediated immunity against HPV16 antigens.
Amyloid-beta vaccine halts Alzheimer’s disease progression in a Phase 2 trial
The Alzheimer’s disease vaccine ABvac40 (Araclon Biotech) improved cognitive score results by 40%, compared to placebo, in 130 subjects enrolled in a randomized, double-blind Phase 2 trial. The treatment was safe and induced robust immune responses.
ABvac40, which targets the Aβ40 peptide that forms amyloid plaques in Alzheimer’s patients, is administered in five monthly doses followed by a booster dose at month 10.
CAR-T cell therapy with cognate vaccine a promising approach in solid cancers
A combination immunotherapy BNT211 (BioNTech) achieved overall response rate of 45% and disease-control rate of 74% in 38 evaluable patients with advanced refractory or relapsed claudin-6-positive solid tumors. BNT211 consists of autologous CAR-T cells targeting the oncofetal antigen claudin-6 and an mRNA vaccine expressing claudin-6 itself to stimulate CAR-T cells’ persistence and activity.
The dose-escalating Phase 1/2 trial reported dose-dependent adverse events, including a cytokine release syndrome in half of the treated patients.
Polyvalent cancer vaccine for treatment of Lynch syndrome demonstrates safety in early trial
The off-the-shelf neoantigen vaccine NOUS-209 (Nouscom) was well tolerated and induced immune responses in 100% of Phase 1b trial participants with Lynch syndrome, a hereditary condition associated with increased risk of developing multiple cancer types.
NOUS-209 consists of adenovirus- and MVA-encoded 209 neoantigens characteristic for microsatellite-instable tumors.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
- Hassel JC, Piperno-Neumann S, Rutkowski P, Baurain JF, Schlaak M, Butler MO, Sullivan RJ, Dummer R, Kirkwood JM, Orloff M, et al. Three-year overall survival with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2023. doi:10.1056/NEJMoa2304753.
- Wadman M. First malaria vaccine slashes early childhood mortality. doi:10.1126/science.adl5503.
- Datoo MS, Dicko A, Tinto H, Ouédraogo JB, Hamaluba M, Olotu A, Beaumont E, Ramos-Lopez F, Magloire Natama H, Weston S, et al. A Phase III randomised controlled trial evaluating the malaria vaccine candidate R21/Matrix-M™ in African children. SSRN [Preprint]. 2023. doi:10.2139/ssrn.4584076.
- Ling AL, Solomon IH, Landivar AM, Nakashima H, Woods JK, Santos A, Masud N, Fell G, Mo X, Yilmaz AS, et al. Clinical trial links oncolytic immunoactivation to survival in glioblastoma. Nature. 2023;623(7985):157–2. doi:10.1038/s41586-023-06623-2.
- Koseki T, Teramachi M, Koga M, Ko MSH, Amano T, Yu H, Amano M, Leyder E, Badiola M, Ray P, et al. A phase I/II clinical trial of intradermal, controllable self-replicating RNA vaccine EXG-5003 against SARS-CoV-2. medRxiv [Preprint]. 2023. doi:10.1101/2023.10.07.23296699.