What work are you leading as KSQ’s Chief Medical Officer?
I'm leading the clinical development organization for KSQ. We have two Phase I/II trials investigating our CRISPR-engineered TIL (eTIL) products, KSQ-001EX and KSQ-004EX. TIL therapy harnesses a patient’s unique, personalized immune response against their own solid tumors: Tumor Infiltrating Lymphocytes, or TIL, are primed by the tumor and equipped to attack it.
We have done a series of genome-wide CRISPR screens and have identified the top two targets which, upon inactivation in TIL, maximizes their function against solid tumors. These targets are SOCS1 and Regnase-1, and when edited in TIL, we see improved engraftment, expansion, tumor infiltration, tumor killing, and long-term persistence in our preclinical models. All of those mechanisms are critical when it comes to improving the ability of TIL to kill tumors, and by inactivating SOCS1 and Regnase-1 in our eTIL therapies, we believe that we can boost efficacy across a variety of solid tumor types with high unmet need. KSQ-001EX is a SOCS1 single-edited eTIL, and KSQ-004EX is a SOCS1/Regnase-1 dual-edited eTIL product.
What common TIL challenges do these two targets help alleviate/overcome?
An important benefit of TIL therapy is the polyclonal nature of the T cell product. TIL leverage a patient’s own immune response against tumor, and have been primed by the patient’s own tumor antigens, leading to a highly polyclonal response which may comprehensively recognize the most important tumor antigens needed for a clinical response. However, because the immunosuppressive nature of solid tumors can limit tumor infiltration, TIL can be exhausted and not functional enough to kill tumor cells. Our CRISPR screens identified SOCS1 and Regnase-1 as driving strong infiltration and accumulation of TIL within tumors. Additionally, our approach with the SOCS1 and Regnase-1 knockouts rescues and functionally enhances TIL to overcome immunosuppression.
"By inactivating SOCS1 and Regnase-1 in our eTIL therapies, we believe that we can boost efficacy across a variety of solid tumor types with high unmet need."
What can you share about KSQ’s approach to TIL product manufacturing?
There is a large body of research on TIL going back many decades. As a result, we were able to build our manufacturing processes based on these learnings from the TIL field. For example, a critical priority for patients is how fast a product can be made available, so we built our process to be fast, with the manufacturing duration of KSQ-001EX and KSQ-004EX being 22 days.
Another challenge with TIL manufacturing—particularly when compared to other known cell therapies like CAR-T cells and TCRs, whose drug product contain a higher percentage of cells that can recognize a target tumor antigen—is variability in the tumor reactive portion of cells within the TIL drug product. It is critical to have enough tumor reactive cells in a TIL drug product.
We know our manufacturing process favorably expands and retains tumor-reactive T cells with the TIL drug product.
Finally, KSQ-001EX and KSQ-004EX are manufactured at CTMC. CTMC is a strong partner to KSQ and we work closely together on our strategy and process. We believe we have the optimal setup to provide engineered, gene-edited TIL therapies (eTIL) in a competitive timeframe.
What decision-making changes guide you as a CMO when focusing specifically on CRISPR-edited TIL therapies?
Any CMO working in cell therapy must take a different approach from other modalities, whether that be other antibodies or small molecules, because it requires a deep knowledge of manufacturing processes to be able to account for the variability in the drug product that is different from patient to patient.
Specifically, with the eTIL platform, we have a strong translational medicine and correlative analysis team that helps us understand all the different aspects of our therapies in the clinic and is instrumental in supporting decisions on adjusting our programs.
Due to the novelty of the SOCS1 and Regnase-1 gene edits in TIL, I have a strong focus on safety. It’s always a critical moment when you have your first-in-human study of something that hasn’t been tested before. There is always a balance between safety and efficacy, in other words, the benefit/risk profile, that needs to be considered.
"If these two edits work in the clinic, they can be applied to multiple therapies independent of target, mechanism or construct."
Can you expand on the impact of patient variability when it comes to the final drug product?
TIL are given at a much higher dose than other cell therapies, like CAR T. CAR T cells are administered in the millions of cells, whereas TIL are given in the range of 1-100 billion cells. T cell quality and quantity in the starting material is very different from patient to patient and may have an impact on the final drug product. In addition, tumor-reactive TIL are only a subset of the drug product that we are infusing.
For example, melanoma has the highest percentage of tumor-reactive cells, between 5-15% depending on the literature. In other, colder cancers, it could be 1% or even less. We have to consider variability tumor-to-tumor, but also patient-to-patient. We believe a benefit of our edits is that because we are enhancing the T cells, we might need fewer of them for efficacy as compared to unmodified TIL therapy.
From a safety perspective, the TIL profile looks different from what we are used to seeing with CAR-T cell therapy. Most of the safety events are related to IL-2 or lymphodepleting chemotherapy. But because TIL have undergone mechanisms of central and peripheral tolerance already, TIL themselves rarely induce toxicities.
Can you walk through the programs in your pipeline, KSQ-001EX and KSQ-004EX and the rationale behind pursuing both concurrently?
As a clinical developer, I feel very strongly that we conduct both studies so we can better determine the contribution and impact of the edits. With KSQ-001EX, we are first testing the SOCS1-edited TIL and in KSQ-004EX, we are testing the Regnase-1/SOCS1 dual-edit. By doing that, we can differentiate the safety profile for each of the programs, and differentiate the efficacy and what Regnase-1 adds on top of SOCS1.
What do you think other developers can gain in knowledge if KSQ’s work with CRISPR-edited TIL is successful?
If we are shown to be successful with the eTIL platform, these edits could technically be added to any T cell therapy – like CAR-T or TCRs – which would be very interesting in the solid tumor space, but also in other areas. If these two edits work in the clinic, they can be applied to multiple therapies independent of target, mechanism or construct.
"Show yourself and what you’re doing. Don’t hide behind your work."
What keeps you passionate about working in IO?
The community and the goal. Everyone working in IO, from the physicians, the scientists, to people working in biopharma, wants to see cancer being cured. We’ve seen a lot of progress, but there’s so much more that we can do, and it makes me passionate. I believe we can cure more patients with cancer, and it’s inspiring to see the science and new ideas that emerge every year. It’s a nice community to work in and to generate progress for patients.
What advice would you give young professionals entering life sciences?
First, be self-confident. Show yourself and what you’re doing. Don’t hide behind your work. Second is connecting. If you have the chance, go and connect. Meet people at posters, find them on LinkedIn, ask questions, etc. One connection might not be sufficient, so try to reconnect with lots of people over time. Third is mentorship. Find people who believe in you and from whom you can seek advice. Sometimes you only realize someone is a mentor in retrospect, but you have to go through the world with open eyes to be able to get advice and see what people are offering you.
