Reprogramming technologies opened the possibility to modify cell identity. We have now applied this concept to induce antigen-presenting dendritic cells and modulate the immune system.
Immunotherapies generate long-term responses against cancer, increasing patient survival. However, important challenges remain and only 20% of patients respond to these therapies.
DIRECT CELL REPROGRAMMING
Cellular reprogramming has highlighted the plasticity of mature cells, providing new technologies to generate any cell type of choice (1-3). Through enforced expression of cell type-specific Transcription factors, proteins able to bind DNA and regulate gene expression, it is possible to reprogram somatic cells to pluripotency or directly into other cell fates of choice. Direct cell reprogramming has proven successful to convert skin cells into other cell types, including blood stem and progenitor cells, neurons, heart and liver cells, using transcription factors specifying target-cell identity (4-6). This technology has been mainly focused in the generation of functional autologous cells for regenerative medicine. Recently, our scientific founders have developed a novel direct reprogramming technology enabling the generation of antigen-presenting dendritic cells from unrelated cells such as skin cells (7). Dendritic cells, also known as professional antigen presenting cells, are immune sentinels that excel on the ability to sense, process and present foreign antigens to immune effector cells, initiating antigen-specific immune responses. This discovery has triggered a paradigm shift in the reprogramming field: for the first time antigen presentation can be programmed by a small combination of transcription factors demonstrating that immune cells and triggered immune responses can be modulated through cell reprogramming.
Cancer immunotherapy employs components of the immune system to fight cancer. In recent years, we have witnessed unprecedented clinical responses with the development of these therapies, awarded with the 2018 Nobel Prize in Physiology or Medicine. In contrast to traditional radiotherapy and chemotherapy, cancer immunotherapies have shown a remarkable benefit by providing long-term responses, increasing patient survival several years after treatment. However, these therapies still face major challenges:
1. Approximately 80% of patients do not respond to cancer immunotherapy. This is related with cancer evasion mechanisms – cancer cells evade immune surveillance by increasing heterogeneity, decreasing the presentation of surface antigens and inhibiting immune cell infiltration. Also, targeted immunotherapy depends on prior antigen identification and do not target the heterogeneous cancer cell population.
2. Autologous cell collection and in vitro manipulation result in extremely high treatment costs.
Thus, there is an urgent need for off-the-shelf cancer-specific immunotherapies that overcome the immune escape mechanisms and the financial struggle associated with the current cancer immunotherapy landscape.
TrojanDC technology is based on an innovative cell reprogramming concept focused on the induction of the dendritic cell fate in cancer cells. Our scientific founders have recently demonstrated for the first time the possibility of generating antigen-presenting dendritic cells by cell reprogramming (7).
Asgard Therapeutics is now developing the world’s first cancer immunotherapy based on dendritic cell reprogramming technology in order to reinstate cancer immunogenicity. TrojanDC is a cancer gene therapy with 2 unique advantages compared with current solutions:
1. TrojanDC will bypass cancer evasion mechanisms: TrojanDC targets the heterogeneity of each tumor forcing individual cancer cells to become immunogenic. TrojanDC reprograms cancer cells to present their own antigens to the immune system, triggering expansion of cancer cell-specific killer T cells and cancer elimination.
2. TrojanDC is an off-the-shelf gene therapy that can be administered to different patients inducing a personalized immune response, which allows competitive production costs when compared with cell-based therapies. It can be applied to several cancers, representing a platform technology with enormous potential.
1. C. F. Pereira, I. R. Lemischka, K. Moore, Reprogramming cell fates: insights from combinatorial approaches. Ann N Y Acad Sci 1266, 7-17 (2012).
2. C. F. Pereira, F. M. Piccolo, T. Tsubouchi, S. Sauer, N. K. Ryan, L. Bruno, D. Landeira, J. Santos, A. Banito, J. Gil, H. Koseki, M. Merkenschlager, A. G. Fisher, ESCs Require PRC2 to Direct the Successful Reprogramming of Differentiated Cells toward Pluripotency. Cell stem cell 6, 547-556 (2010).
3. C. F. Pereira, R. Terranova, N. K. Ryan, J. Santos, K. J. Morris, W. Cui, M. Merkenschlager, A. G. Fisher, Heterokaryon-based reprogramming of human B lymphocytes for pluripotency requires Oct4 but not Sox2. PLoS genetics 4, e1000170 (2008).
4. A. M. Gomes, I. Kurochkin, B. Chang, M. Daniel, K. Law, N. Satija, A. Lachmann, Z. Wang, L. Ferreira, A. Ma’ayan, B. K. Chen, D. Papatsenko, I. R. Lemischka, K. A. Moore, C.-F. Pereira, Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming. Cell Reports 25, 2821-2835.e2827 (2018).
5. C. F. Pereira, B. Chang, A. Gomes, J. Bernitz, D. Papatsenko, X. Niu, G. Swiers, E. Azzoni, M. F. de Bruijn, C. Schaniel, I. R. Lemischka, K. A. Moore, Hematopoietic Reprogramming In Vitro Informs In Vivo Identification of Hemogenic Precursors to Definitive Hematopoietic Stem Cells. Developmental cell 36, 525-539 (2016).
6. C. F. Pereira, B. Chang, J. Qiu, X. Niu, D. Papatsenko, C. E. Hendry, N. R. Clark, A. Nomura-Kitabayashi, J. C. Kovacic, A. Ma’ayan, C. Schaniel, I. R. Lemischka, K. Moore, Induction of a hemogenic program in mouse fibroblasts. Cell stem cell 13, 205-218 (2013).
7. F. F. Rosa, C. F. Pires, I. Kurochkin, A. G. Ferreira, A. M. Gomes, L. G. Palma, K. Shaiv, L. Solanas, C. Azenha, D. Papatsenko, O. Schulz, C. R. e Sousa, C.-F. Pereira, Direct reprogramming of fibroblasts into antigen-presenting dendritic cells. Science Immunology 3, eaau4292 (2018).
Video credit: Jonas Ahlstedt & Sebastian Wasserstrom/Lund University Bioimaging Center