Current development in adenoviral vectors for cancer immunotherapy

Abstract

Adenoviruses are well characterized and thus easily modified to generate oncolytic vectors that directly lyse tumor cells and can be "armed" with transgenes to promote lysis, antigen presentation, and immunostimulation. Oncolytic adenoviruses (OAds) are safe, versatile, and potent immunostimulants in patients. Since transgene expression is restricted to the tumor, adenoviral transgenes overcome the toxicities and short half-life of systemically administered cytokines, immune checkpoint blockade molecules, and bispecific T cell engagers. While OAds expressing immunostimulatory molecules ("armed" OAds) have demonstrated anti-tumor potential in preclinical solid tumor models, the efficacy has not translated into significant clinical outcomes as a monotherapy. However, OAds synergize with established standards of care and novel immunotherapeutic agents, providing a multifaceted means to address complexities associated with solid tumors. Critically, armed OAds revitalize endogenous and adoptively transferred immune cells while simultaneously enhancing their anti-tumor function. To properly evaluate these novel vectors and reduce the gap in the cycle between bench-to-bedside and back, improving model systems must be a priority. The future of OAds will involve a multidimensional approach that provides immunostimulatory molecules, immune checkpoint blockade, and/or immune engagers in concert with endogenous and exogenous immune cells to initiate durable and comprehensive anti-tumor responses.

Advancing together and moving forward: Combination gene and cellular immunotherapies

“…Biegert et al 12 reviewed the current landscape of oncolytic adenoviruses for the treatment of cancer, focusing on the benefits of both genetic modifications to arm viruses with various modalities, including immunostimulatory molecules and immune checkpoint blockade, as well as rational combinations with standard of care or immunotherapies that enhance anti-tumor immunity. One example of genetic modifications to oncolytic adenovirus therapy, presented in this issue by O'Connell et al, 13 incorporates a selfligand receptor SLAMF7-Fc fusion protein or its intracellular adaptor, EAT-2, into the virus to augment oncolytic virus activity in solid tumors.…”

An engineered ligand-responsive Csy4 endoribonuclease controls transgene expression from Sendai virus vectors

“…However, these DNA-based vectors have critical disadvantages with regards to long-term durability of transgene expression [ 5 ], the maximum size of a packageable transgene [ 6 ], or a potential risk of tumor formation by the integrated transgene [ 7 ]. Despite extensive studies on other types of DNA-based viral vectors, including adenoviral vectors (AdV) [ 8 ], very few DNA-based vectors are available that enable durable expression of a large transgene without the risk of chromosomal integration. Alternatively, other choice of vectors for gene delivery includes RNA-based vectors, which exist in cells as RNA and do not integrate into the host genome [ 9 ].…”

Mesenchymal stromal cells protect combined oncolytic and helper-dependent adenoviruses from humoral immunity

“…In CAdVEC, the oncolytic component (OAd) serves a secondary purpose beyond direct tumor cell destruction by facilitating replication and amplification of a separate helper-dependent (HDAd) virus encoding immunostimulatory transgenes to boost anti-tumor immune responses. 14 …”