Cancer vaccines hold immense potential in revolutionizing cancer treatment, offering a beacon of hope for patients worldwide. In the quest for effective cancer vaccines, various avenues have been explored, including the use of dendritic cells (DCs) as ex vivo manufactured antigen-presenting cells (APCs). While DCs have shown limited effectiveness, their clinical development was hampered by various challenges including the scarcity of DC progenitors in the bloodstream of donors/patients as well as manufacturing-related hurdles. These limitations pushed scientists to seek alternative cellular platforms, which brought forward the possible use of mesenchymal stromal cells (MSCs). Interestingly, MSCs are: i) versatile in their application, ii) easily accessible from several tissue sources, and iii) demonstrated safety in clinical studies.
For this groundbreaking study, lead researcher Dr. Moutih Rafei from Université de Montréal collaborated with his colleagues at Defence Therapeutics to enhance the effectiveness of cancer vaccines by leveraging MSCs as APCs. To achieve this, they revamped the Accum® technology, which was initially designed to enhance drug delivery for effective intracellular accumulation. The use of this technology led to the discovery of a yet unprecedented property for Accum® and its derivatives in reprogramming MSCs to behave as APCs capable of cross-presenting antigens. This approach resulted in robust stimulation of immune response against cancer; observations that were recently published in the peer-reviewed journal, iScience.
By utilizing the Accum® technology, Dr. Rafei and his team generated an Accum® variant (referred to as A1) capable of inducing potent antigen cross-presentation in MSCs. When tested in animals, these cells showed promising results in triggering the immune system to fight cancer cells. “Overall, our data indicate a central role for A1 on various cross-presentation-related processes such as antigen uptake, escape to the cytosol and subsequent processing by the proteasomal machinery,” Dr. Rafei notes. While examining various molecular processes, A1 was found to elicit intra-endosomal reactive oxygen species production causing endosomal membrane breaks via lipid peroxidation. Dr. Rafei and his team also studied how A1 affected MSCs and found changes in several biological pathways including cell stress responses and metabolism, as well as the release of pro-inflammatory mediators. The sum of these observations led them to call this vaccine A1-Reprogrammed-MSCs (ARMs). “The ARM cells induce potent antitumoral responses, as shown in a series of vaccination studies conducted on animals with pre-established solid tumors. This innovative approach resulted in a large set of animals exhibiting complete responses (e.g. tumor eradication),” Dr. Rafei further explains. Their study not only proposes an alternative mode of vaccination, utilizing MSCs as the base ingredient, but it also shows how the ARM vaccine can be adapted to the generation of a broader scope of cancer vaccines targeting multiple other indications.
The pursuit of effective cancer vaccines resulted in significant strides, with MSCs emerging as a promising platform. Dr. Rafei and his team showcased the potential of leveraging MSCs as APCs through the innovative use of the Accum® technology. “Overall, our findings convey two important messages. First, the ARM vaccine can indeed induce potent antitumoral responses even when pulsed with tumor lysate. Second, the developed approach is versatile and can be adapted to different cancer types if given access to tumor tissues/biopsies,” Dr. Rafei concludes. This innovative approach not only holds promise in surmounting the challenges of traditional cancer vaccines, but also marks a transformative shift in immunotherapy, opening up a compelling avenue for effective cancer treatment and prevention in the future. Furthermore, its versatility makes it adaptable to a wider array of cancer types, thereby paving the way for a more hopeful future in the ongoing battle against cancer.
JOURNAL REFERENCE
Marina Pereira Gonçalves, Roudy Farah, Jean-Pierre Bikorimana, Jamilah Abusarah, Nehme EL-Hachem, Wael Saad, Sebastien Talbot, Daniela Stanga, Simon Beaudoin, Sebastien Plouffe, Moutih Rafei. “A1-reprogrammed mesenchymal stromal cells prime potent antitumoral responses.” iScience, 2024.
DOI: https://doi.org/10.1016/j.isci.2024.109248.
ABOUT THE AUTHOR
Dr. Moutih Rafei is an immunologist by training focused on the development of therapies within the immuno-oncology space. Throughout the past decade, he accumulated profound knowledge and insight in the fields of T-cell development, stem cell biology, cancer immunotherapy and autoimmune diseases. While completing his PhD in Experimental Medicine at McGill University, Dr. Rafei worked on various projects including the development of novel fusokines while being exposed to the biology of mesenchymal stromal cells and ways to exploit these cells as cellular therapeutics for several indications. Following his PhD, he then completed a post-doctoral fellowship in Molecular Biology at Université de Montréal, where investigated the impact of cytokines on intrathymic T-cell development. His studies lead to the seminal discovery of new role for interleukin-21 in supporting de novo T-cell development. Starting on this strong basis, he established in 2013 his laboratory at Université de Montréal focusing on ways to stimulate T-cell development and activity. So far, he is considered as a leader in the development of immune-related therapies for catastrophic illnesses with many uncovered seminal discoveries, some of which are currently being tested in clinical trials. So far, Dr Rafei received over 20 awards and recognitions and his research has resulted in over 50 high impact peer-reviewed publications, 5 reviews, 2 book chapters, 1 monograph, and 6 patents. Dr. Rafei trained a long list of highly qualified personnel and secured millions in grants over the last 10 years as an independent principal investigator. He is is continuously striving both academically and industrially to consolidate his growing leadership to further develop his innovative research program while making fundamental and translational breakthroughs in the field of immunology-oncology.
