Diallo Lab

Our research team is dedicated to exploring and advancing the field of "viral sensitizer" drugs, which enhance cellular susceptibility to viral medicines. Our primary objective is to leverage these innovative drugs for a wide range of virus-based therapeutic applications, such as cancer and gene therapy, and to enhance vaccine biomanufacturing methods. 
 

The Challenge

Cellular antiviral defenses can hinder the effectiveness of viral therapeutics, be it oncolytic viruses, gene therapy vectors, or viral vaccines. For instance, antiviral defenses within tumors can lead to the failure of oncolytic virus-based treatments. Similarly, these defenses can hinder productivity in the manufacturing of cell-based viral vaccines and reduce transduction efficiency and transgene expression in gene therapy endeavors.

Small molecule viral enhancers (Viral Sensitizers)

To overcome these hurdles, we have embarked on an innovative journey. By employing cutting-edge technology including high-throughput robotics, we have conducted several extensive screens, leading to the discovery of a number of remarkable compounds known as "viral sensitizers" or VSes. Our research, spanning several publications, has demonstrated that these VSes have the extraordinary potential to boost virus output from cells multiple fold. While acting through distinct mechanisms, we have demonstrated that these VSes can effectively neutralize cellular antiviral defenses and increase oncolytic virus therapy in several preclinical cancer models. Our ultimate goal is to leverage this knowledge to develop even more potent viral enhancers for diverse manufacturing and therapeutic applications. These viral sensitizers are not limited to any single type of viral therapeutic – preselected and combined, they have the potential to enhance oncolytic viruses, gene therapy vectors, and viral vaccines.

Revolutionizing cancer immunotherapy

Cancer immunotherapies represent a groundbreaking approach in the field of oncology, offering new hope for cancer patients by harnessing the power of the immune system to combat cancer. Our lab is interested in advancing oncolytic virotherapies and adoptive cell therapies using VSes and other facilitating agents. Oncolytic viruses (OV) have made tremendous strides as viable therapeutics for cancer patients in recent years with a handful approved to date and many others in various phases of clinical evaluation. However, like most therapies, heterogeneity of treatment response to OVs remains a major challenge. Our lab is working on developing strategies to transiently suppress antiviral defenses thereby allowing OVs to gain a foothold for increased infectivity and therapeutic efficacy. We have discovered several small molecule viral sensitizers that possess the unique ability to enhance the activity of oncolytic viruses specifically within tumor cells thereby conferring therapeutic benefit in several different mouse models of cancer and human patient samples. We have also demonstrated that these viral sensitizers can be targeted to the tumour compartment using antibody-drug conjugate (ADC) technology. As proof of concept, we have shown remarkable synergy between oncolytic viruses and the clinically approved ADC targeting human HER2, trastuzumab emtansine (T-DM1 or Kadcyla). For the evaluation of immune impacts of our therapy, our lab has developed novel syngeneic mouse models of human HER2+ cancer, using a truncated form of huHER2. The use of VSes and the knowledge gained from our understanding of their impact on antiviral pathways can allow for the design of optimized cancer immunotherapy stategies for clinical testing.

Viral Sensitizers for Global Health

Viral sensitizers also hold the potential to transform the landscape of viral therapeutic production. The demand for vaccines continues to surge, placing immense pressure on vaccine manufacturers and governments worldwide, especially during pandemics. Viral enhancers show a promise of significantly improving manufacturing yields.

Partnering for Progress

Our discoveries have spurred significant commercialization activity. Our team places a significant focus on knowledge translation activities, and as a result, our research has resulted in the creation of multiple patents and spinout companies. This has led to partnerships geared toward both manufacturing applications and immunotherapy applications of this unique technology, thereby paving the way for transformative advancements in medical treatments. In addition to our expertise in high throughput screening, we have also acquired through CFI a 220K library of synthetic compounds available for academic researchers within Ontario.

Taha Z, Crupi MJF, Alluqmani N, MacKenzie D, Vallati S, Whelan JT, Fareez F, Alwithenani A, Petryk J, Chen A, Spinelli MM, Ng K, Sobh J, de Souza CT, Bharadwa PR, Lee TKH, Thomas DA, Huang BZ, Kassas O, Poutou J, Gilchrist VH, Boulton S, Thomson M, Marius R, Hooshyar M, McComb S, Arulanandam R, Ilkow CS, Bell JC, Diallo JS. Complementary dual-virus strategy drives synthetic target and cognate T-cell engager expression for endogenous-antigen agnostic immunotherapy. Nat Commun. 2024 Aug 23;15(1):7267.

Jirovec A, Flaman A, Godbout E, Serrano D, Werier J, Purgina B, Diallo JS. Immune profiling of dedifferentiated liposarcoma and identification of novel antigens for targeted immunotherapy. Sci Rep. 2024 May 16;14(1):11254.

Alwithenani A, Taha Z, Thomson M, Chen A, Wong B, Arulanandam R, Diallo JS. Unlocking the potential of dimethyl fumarate: enhancing oncolytic HSV-1 efficacy for wider cancer applications. Front Immunol. 2023 Dec 19;14:1332929.

Wong B, Bergeron A, Maznyi G, Ng K, Jirovec A, Birdi HK, Serrano D, Spinelli M, Thomson M, Taha Z, Alwithenani A, Chen A, Lorimer I, Vanderhyden B, Arulanandam R, Diallo JS. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, sensitizes cancer cells to VSVΔ51 oncolytic virotherapy, Mol Ther, 2023 Sep 27: S1525-0016(23)00504-X.

Taha Z, Arulanandam R, Maznyi G, Godbout E, Carter-Timofte ME, Kurmasheva N, Reinert LS, Chen A, Crupi MJF, Boulton S, Laroche G, Phan A, Rezaei R, Alluqmani N, Jirovec A, Acal A, Fekete EEF, Singaravelu R, Petryk J, Idorn M, Potts KG, Todesco H, John C, Mahoney DJ, Ilkow CS, Giguère P, Alain T, Côté M, Paludan SR, Olagnier D, Bell JC, Azad T, Diallo JS. Identification of FDA-approved bifonazole as a SARS-CoV-2 blocking agent following a bioreporter drug screen, Mol Ther, 2022 Sep 7;30(9):2998-3016.

Arulanandam R, Taha Z, Garcia V, Selman M, Chen A, Varette O, Jirovec A, Sutherland K, Macdonald E, Tzelepis F, Birdi H, Alluqmani N, Landry A, Bergeron A, Vanderhyden B, Diallo JS. The strategic combination of trastuzumab emtansine with oncolytic rhabdoviruses leads to therapeutic synergy. Commun Biol. 2020 May 22;3(1):254.