Innovating In Vivo Cell Therapies: A New Era in Cancer Treatment
Written on
Chapter 1: Introduction to Axial Discovery
Axial Discovery is dedicated to collaborating with visionary founders and innovators. We focus on investing in nascent life sciences companies, including Appia Bio, Seranova Bio, and Delix Therapeutics, often at the conceptual stage. Our mission is to support the exceptional inventor eager to establish a lasting enterprise. If you or someone you know has a groundbreaking idea in the life sciences sector, we would love to connect and potentially invest in your vision. Reach out to us at [email protected].
Chapter 2: The Promise of In Vivo Cell Therapies
A significant opportunity exists to modify immune cells in situ for the treatment of cancer and other conditions. One challenge with CAR-T cell therapy is the phenotypic variability of tumors, which can lead to immune escape variants that evade detection by targeting receptors. By programming lymphocytes with chimeric antigen receptors (CAR) that can identify various tumor antigens, we may overcome this issue. However, creating a comprehensive range of T-cell variants using current ex vivo techniques remains impractical.
Injectable agents that program T-cells in vivo could provide a straightforward method to swiftly generate immunity against any targetable tumor antigen. The Mooney Lab at Harvard/Wyss Institute holds significant intellectual property in this area, enabling fine-tuning of multiple T-cell specificities to match the unique antigenic profile of each patient's tumor. Additionally, in vivo therapies eliminate supply chain challenges and the need for preconditioning, which is also beneficial for B-cell treatments.
Key Components of In Vivo Cell Therapy
Essential elements for effective in vivo cell therapy include:
- Delivery Vector: Options such as lentiviral vectors (as used by Umoja), nanoparticles, and HSVs must prioritize safety and manufacturing ease, ideally requiring only a limited number of doses.
- Payload: This is the actual content transformed into an immune cell, which needs to be compatible with the chosen vector.
- Shared Biology: A given vector's success likelihood improves over time across different payloads.
The current frontrunners in this domain include Interius Biotherapeutics, stemming from Saar Gill's Lab at Penn, and Umoja Biopharma, primarily based on Michael Jensen's research at Fred Hutch. Yvonne Chen's Lab at UCLA is also making strides, establishing her as a leading figure in this field.
Understanding T-Cell Exhaustion
An important aspect of cell therapies lies in identifying both the activating and inhibitory components. Exhausted T-cells (Tex) are categorized into two main subsets: progenitor and terminally differentiated. These T-cells can remain functionally active yet reach a standoff with cancer or pathogens, presenting an opportunity to reverse this exhaustion. There is a critical need for a more comprehensive understanding of the distinct subsets of exhausted T cells, their diversity, and the underlying epigenetics.
Common features of T-cell exhaustion include progressive loss of effector functions, sustained upregulation and co-expression of multiple inhibitory receptors, alterations in key transcription factors, metabolic disruptions, and difficulties in transitioning to a quiescent state. Addressing these areas presents significant prospects for designing innovative cell therapies.
For instance, Lyell is utilizing c-Jun overexpression techniques from the Mackall Lab at Stanford to counteract T-cell exhaustion. Their therapy recently received IND clearance for treating solid tumors, an exciting development to monitor.
Additional Research in the Field
Several research initiatives are currently underway, including:
- The Poojary Lab's work on deleting Cbl-b to reverse T-cell exhaustion.
- Wherry Lab's discovery of the transcription factor TOX as a key player in T-cell exhaustion.
- The Oldstone Lab's efforts at Scripps focused on small molecule screening aimed at reversing T-cell exhaustion.
A compelling case study from the Wherry Lab investigates whether exhausted CD8+ T-cells can regain normal function after the removal of chronic antigenic stimulation. This research could extend to tumor exposure, with insights gained from using the mouse virus LCMV to induce T-cell exhaustion. Post-transplantation of Texs into non-infected mice without antigen exposure showed that while most Texs perished, the few survivors exhibited some gene expression profiles akin to normal memory T-cells, although they remained largely exhausted with stable epigenetic modifications.
This foundational work aids in understanding T-cell exhaustion and discovering new methods to reverse it. For effective in vivo therapies, this information is crucial for designing treatments that can counter tumor evasion and maximize the potential of transforming immune cells in situ, thereby expanding treatable indications and enhancing patient response rates.
Chapter 3: Call for Talent and Collaboration
We are actively seeking new talent, whether you are an inventor, operator, product manager, or engineer. The field of cell therapies requires innovative approaches with a focus on novel platforms and scalable business models. Axial is poised to provide investment along with access to our network of founders, executives, and a dedicated team of venture partners. We are particularly enthusiastic about epigenetic reprogramming to convert Texs into effector/memory T-cells in vivo. If you're interested in collaborating, please reach out at [email protected].
The first video, "Scientist Stories: Saar Gill, CAR-T Cell Therapies," shares insights from Saar Gill on the development and impact of CAR-T cell therapies in treating cancer.
The second video, "In Vivo CAR T-Cell Therapeutics With Umoja Biopharma's Dr. Andrew Scharenberg," explores the advancements and future of in vivo CAR-T cell therapies, featuring Dr. Scharenberg's innovative work.