What’s Next for Immunotherapies?

It’s always energizing to catch up with Mark, as he has a deep-rooted passion for bringing innovative immunotherapies to more people living with cancer. Through a mix of external and internal innovation, his team has forged remarkable partnerships and advancements that could take immunotherapy to new heights.

Mark, in our previous interview, we spoke about the promise of T cell engagers (TCEs) in hematology. Since then, you’ve taken TCEs to the next level with AstraZeneca’s proprietary next-generation T cell engager platform, Target Induced T cell Activating Nanobody (TITAN). Can you tell me more about this platform?

?Yes, of course, Anas. I always enjoy discussing the science with you. The TITAN platform emerged from our discovery teams and is designed to address challenges in development, for example, cytokine release syndrome (CRS) that is often associated with TCE therapy and limits the dose that can be given. The challenge is that many current TCEs activate all types of T cell, however, the CD4+ subtypes secrete cytokines that can lead to CRS.

?To solve this problem, we asked, “What would make a better engager?” and “What T cells do we want to engage?”.

?So, we designed a selective engager that would only activate the cytotoxic CD8+ T cells, the ones that have the ability to kill cancer cells. By minimizing the activation of CD4+ T cells we aim to increase the specificity of the anti-cancer immune response.

?Secondly, by engaging with a reduced fraction of T cells – only the CD8+ subset - TITAN potentially reduces the overall level of cytokines activated, which could also minimize unwanted side effects.

That not only sounds very exciting but also very logical. I wonder why this didn’t happen earlier?

?I suspect this is because it was quite tough to achieve. Through trial and error, and being agile, we moved away from modalities that did not work to our rationally designed TITAN platform. We hope that as we continue to research TITAN TCEs, the result will deliver a more targeted immune response against cancer.

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That really exemplifies how persistence can pay off! I want to expand on the selective recruitment of CD8+ cells with TCEs and the advantage we briefly discussed. Do you think CAR T cells will move towards CD8+ selective T lymphocytes, or is this unique for TCEs?

?I like to think that anything is possible when it comes to cell therapy. Certainly, there are efforts in the field to look at CD4+ and CD8+ composition. We’ve known for some time, in the context of stem cell transplantation and allogeneic T cells, that the CD4 T cell compartment is extremely important for maintaining the functionality of CD8+ T cells.1 Whether we can have an entirely CD8+ selective process I’m not sure. But seeing the rate of innovation in gene editing and engineering, I think with time this could be possible.

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Exciting milestones are on the horizon for the team. As we know, there is a lot of investment in cell therapy across the industry. We recently acquired Gracell Biotechnologies, which enriched our growing pipeline with a CAR-T cell therapy. As the head of cell therapy discovery, how does this acquisition fit into our broader cell therapy strategy?

?That’s a great question. We’ve been delighted with the acquisition of Gracell. They’re a very ambitious company; they are true innovators willing to push the boundaries of science, which really complements our ambition.

?As you know Anas, manufacturing autologous CAR-Ts involves isolating and editing a patient’s T cells to recognize their tumor2, which is a lengthy process. There’s a general trend in the field toward finding solutions to overcome these challenges. Gracell has invested a lot of time in driving innovations to optimize the process and has created something quite unique, a platform that enables T cells to be manufactured in just 24 hours. The T cells are in the lab for a much shorter period of time, so are considered ‘younger’ and potentially more effective, which is really important in cell therapy. This also potentially reduces the overall time a patient has to wait for their medicine to be created. ?

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Excellent. What innovations are you most excited about in cell therapy that could overcome some of the barriers to their widespread adoption? And what do you think the future of cell therapy looks like in cancer treatment, in general?

?I’m very excited by “off-the-shelf platforms,” or allogeneic cancer cell therapies, that use cells from healthy donors rather than individual patients.3 We’re not treating enough people who could benefit from CAR-Ts due to global manufacturing capacity and economic issues that limit their provision.4 There is a strong drive across the industry to make cancer cell therapies more scalable and accessible, and we hope to develop “off-the-shelf” therapies to achieve this.

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That would be quite an accomplishment. Cell therapy is making a major impact on patients with various hematological malignancies. Any final words?

?Well, although we still have some way to go to realize the full potential of cell therapy, innovation is moving at such a fast pace I believe there are exciting times ahead, so watch this space!

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?References:

1.?????? Ogonek J, Kralj Juric M, Ghimire S, et al. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2016;7:507.

2.?????? Sheykhhasan M, Ahmadieh-Yazdi A, Vicidomini R.?et al.?CAR T therapies in multiple myeloma: unleashing the future.?Cancer Gene Ther. 2024;31:667–686.

3.?????? Saultz JN, Otegbeye F. Optimizing the cryopreservation and post-thaw recovery of natural killer cells is critical for the success of off-the-shelf platforms.?Front Immunol. 2023;14:1304689.

4.?????? Gajra A, Zalenski A, Sannareddy A, et al. Barriers to Chimeric Antigen Receptor T-Cell (CAR-T) therapies in clinical practice. Pharmaceut Med. 2022;36(3):163-171.