title: Interesting possibilities to improve the safety and efficacy of ipilimumab (Yervoy).
abstract: As predicted, an anti-CTLA-4 mAb (ipilimumab) on binding to T lymphocytes breaks down immune-tolerance. Thereby, it was hoped, tumor-specific-T cells would be freed for a sustained attack on cancer cells. Data on ipilimumab treatment in 1498 patients with advanced melanoma (in 14 phase I-III trials) has shown immune-related adverse events (irAEs) in 64.2% of the patients consistent with tolerance breakdown. However, there is no evidence that the antitumor effects via a CTLA-4 blockade are attributable to T cells specifically targeting tumor cells. In fact, several trials indicate a possible correlation between grade 3 and 4 irAEs with clinical efficacy of ipilimumab; tumor regression may be associated with autoimmunity development. Therefore, we suggest a new treatment paradigm. The non-tumor specific pan-lymphocytic activation should be exploited by a 'pretargeting' approach proven successful in radioimmunodetection and radioimmunotherapy. First, an anti-tumor mAb conjugated with streptavidin (StAv) should be administered to be followed by the delivery of biotin-labeled anti-CTLA-4 mAb. This schedule has the virtue of endowing T cells with the ability to travel to tumor sites without prematurely succumbing to apoptosis, while streptavidin's ultra-high affinity for biotin (K(D), 10⁻¹⁵ M) ensures capturing all T cells binding biotin labeled anti-CTLA-4. Using the law of mass action, we calculated that following administration of ipilimumab at >1 mg/L concentration (∼5 mg per patient ∼70 kgbw), the immense forces of the immune system liberated by the anti-CTLA-4 antibody blockade would then be focused with laser sharp accuracy on tumor cells without collateral damage to normal host cells.
authors.affiliation: Department of Probability, Alfred Renyi Institute of Mathematics, Hungarian Academy of Sciences, Realtanoda Utca 13-15, H-1053 Budapest, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Bakacs
authors.forename: Jitendra N
authors.initials: JN
authors.lastname: Mehrishi
authors.forename: Miklós
authors.initials: M
authors.lastname: Szabó
authors.forename: Ralph W
authors.initials: RW
authors.lastname: Moss
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D006801:Humans; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D010455:Peptides / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; D010455:Peptides