Abstract
Cancers represent highly significant health issues and the options for their treatment are often not efficient to cure the disease. Immunotherapy strategies have been developed to modulate the patient’s immune system in order to eradicate cancerous cells. For instance, passive immunization consists in the administration at high doses of exogenously produced monoclonal antibodies directed either against tumor antigen or against immune checkpoint inhibitors. Its main advantage is that it provides immediate immunity, though during a relatively short period, which consequently requires frequent injections. To circumvent this limitation, several approaches, reviewed here, have emerged to induce in vivo antibody secretion at physiological doses. Gene delivery vectors, such as adenoviral vectors or adeno-associated vectors, have been designed to induce antibody secretion in vivo after in situ cell modification, and have driven significant improvements in several cancer models. However, anti-idiotypic antibodies and escape mutants have been detected, probably because of both the continuous expression of antibodies and their expression by unspecialized cell types. To overcome these hurdles, adoptive transfer of genetically modified B cells that secrete antibodies either constitutively or in a regulated manner have been developed by ex vivo transgene insertion with viral vectors. Recently, with the emergence of gene editing technologies, the endogenous B cell receptor loci of B cells have been modified with the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonuclease (Cas-9) system to change their specificity in order to target a given antigen. The expression of the modified BCR gene hence follows the endogenous regulation mechanisms, which may prevent or at least reduce side effects. Although these approaches seem promising for cancer treatments, major questions, such as the persistence and the re-activation potential of these engineered cells, remain to be addressed in clinically relevant animal models before translation to humans.
Highlights
Cancers remain a highly significant health burden, causing around 10 million deaths per year, which represent the second leading cause of death worldwide according to the WorldHealth Organization, after cardiovascular diseases
While the approaches to induce in vivo antibody secretion have greatly evolved, they currently only partially address the hurdles of passive antibody infusion
Adenoviral and lentiviral vectors encoding antibodies were used to induce the expression of more physiological concentrations of antibodies, avoiding side effects associated to huge antibody doses
Summary
Cancers remain a highly significant health burden, causing around 10 million deaths per year, which represent the second leading cause of death worldwide according to the World. Immune checkpoint activators, such as immunostimulatory anti-OX40 antibodies, have been developed to increase the activation and effector functions of the immune system against cancer cells [6,7] These strategies require some improvements especially to predict patients who can respond [8]. The main drawback often associated to such therapies is that it only provides short-term protection, owing to the relatively short half-life of Abs. except when using immune checkpoint blockers that can enhance pre-existing anti-tumor immunity, no memory responses are usually induced following monoclonal antibody infusion. This strategy was initially investigated in preclinical studies for chronic diseases induced by infectious pathogens (e.g., human immunodeficiency virus, HIV [19] and simian immunodeficiency virus, SIV [20], hepatitis C virus, HCV [21]), it was more recently translated to other pathologies, such as cancers
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