T Cell Engagers, Moving Beyond Pembrolizumab, and Medicine Development for Future Patients, with Roche's Ashley Lakner
Ashley Lakner, Head, Oncology Discovery - pRED Oncology, Roche, discusses the modalities they’re most interested in, their work moving beyond established checkpoint inhibitors and understanding immunogenicity, and the challenges in designing drugs for the patient of the future, amongst other topics.
What are your areas of focus and tumor types of interest?
The tumor types we’re focused on are lung, breast and malignant heme. We also have a strong emphasis on colorectal cancer, because there have been more and more cases of earlier diagnosed colorectal cancer, but nominal improvements in patient care over the past 30 years.
We’re also very interested in looking inside the tumor cell to understand hallmarks of cancer using different or novel modalities to do so. We also work on intracellular oncogenic dependencies, whether that’s key mutations or key growth signaling pathways.
What are the modalities you’re working with?
In terms of modalities, we use a highly diverse toolbox, including small molecule inhibitors, molecular glues, degraders, large molecules, bispecifics and trispecifics. It’s been recently announced that Roche has made some large plays in allogeneic CAR T with our acquisition of Poseida. We try to remain agnostic to the modality and focus on what tools we think would be the best to employ based on the target and tumor biology.
One area of focus is T cell engagers, specifically unlocking them for solid tumors. Another is identifying what will be the most promising therapy following classical checkpoint inhibitors. Following pembrolizumab, we want to understand what comes next for those patients, and we want to understand responders/non-responders.
"When we think about harnessing the power of the T cell, we know that we should be able to elicit deeper, more durable responses with a more tolerable molecule than is currently possible with some of the existing therapies that are out there."
What can you tell us about your research into TCEs?
While we’ve seen other powerhouse drugs come on the market for key indications – the ADC Enhertu for breast cancer, for example – they don’t come without a very severe toxicity profile for certain patients and in some cases it is too early to comment on the durability of the response.
When we think about harnessing the power of the T cell, we know that we should be able to elicit deeper, more durable responses with a more tolerable molecule than is currently possible with some of the existing therapies that are out there. In the heme space, there have been beautiful proofs of concept that show you can achieve great response with ADAs, without immunogenicity. We’ve yet to unlock that for the solid tumor space.
What is one challenge you’re addressing that could help us make meaningful clinical progress?
One challenge that all of us in the field face is immunogenicity. Patients treated with biologics are at risk of developing antidrug antibodies (ADAs) during therapy. ADAs may affect pharmacokinetics, patient safety, and treatment efficacy. Through modeling and reverse translation work, we are interested in more accurately predicting the effect on PK and ultimately how immunogenicity may prohibit a patient from responding to a drug. This challenge is inherent to the biology we’re focusing on in our programs and won’t likely be solved in the next few years, so trying to get better at compartmentalizing and understanding where the immunogenicity is coming from is key. There has been evolution in terms of in silico prediction and digital tools to examine sequence-related immunogenicity, to better understand where it comes from and how to optimize it.
Another focus is what’s next for patients after checkpoint inhibitors, to provide a new therapy for patients who are benefitting and understand who the unserved patients are to exploit that resistance. There is still so much we don’t understand about the biomarkers for selecting those patients who will respond.
And finally, T cell exhaustion is a significant topic on our radar. We and others have seen that we do not truly understand exhaustion biology and the clinical consequences, so we are taking it back to basic biology to understand ways of preventing T cell exhaustion in pre-clinical studies utilizing novel in vitro systems and assays.
What are the technologies that are the most helpful to you in your work?
In PRED Oncology, we are harnessing the power of patient-derived organoids and explants. They allow us to depict a more pathophysiologically relevant state of disease beyond a 2-D model, with only certain genes or proteins expressed. We have immense expertise in humanized mouse models and will continue to explore alternatives to replace murine models where possible.
In addition to that, we have made strategic partnerships in the past couple of years focused on computational biology. With that, we are trying to look at protein-protein interaction interfaces in a different way or use in silico tools to predict drug sensitivity based on certain genetic signatures.
When you think about developing a molecule for the patient of the future, how does that guide your work?
One of our guiding statements is doing now what patients need next, with aggressive anticipation of how the standard of care and treatment paradigms are going to change over the next couple of years. For every patient population we are asking what the current drugs on the market are, what the response rate is, how we can better understand where resistance will occur, etc, based on modeling how their tumor microenvironment changes.
Using patient-derived samples and organoids that have been exposed to certain lines of prior therapy, we are trying to look at how patients would respond to new drugs.
Other efforts focus on harnessing basic molecular biology research to understand early disease. Right now, most of us are treating late-line disease and highly metastatic patients. But what about a patient who is in Stage 1? What were the initial molecular events and signatures? Does their tumor look very different from the tumor that I'm treating in a Stage 3 or Stage 4 setting?
Detection goes hand-in-hand with treating earlier. That is where our work in imaging, and strength in diagnostics is extremely helpful.
"One of our guiding statements is doing now what patients need next, with aggressive anticipation of how the standard of care and treatment paradigms are going to change over the next couple of years."
How has the success of checkpoint blockades influenced your approach to the next phase of CPI?
Current CPI drugs have certainly made an impact, but there are other parameters that also matter. There is still so much biology that we don’t understand that we don’t need to seek to compete or match MoA with CPI on all levels. If you can, for example, provide a better response rate for a patient, then we can talk about dose, schedule, etc. It can be that we don’t need 100% checkpoint blockade to achieve the efficacy we want. We’re actually seeing data supporting that biological hypothesis with some of the new PD-1-directed cytokines.
Another thing to remember is that there are still patients who don’t respond to CPI or who become very quickly refractory. I want to make sure that we are acknowledging and working towards that unmet need. We must be cautious about benchmarking everything off of current CPI and using that as the only marker for success as we progress programs.
What do you want folks to keep in mind as we develop drugs for the future?
To remember the interplay between the tumor and the tumor microenvironment, but also the systemic human biology. Everything has pathways that intertwine. And if we’re successful with T cell engagers in solid tumors, what comes next for those patients? How long can you keep engaging T cells and what are the novel combinations? We have not fully exploited the power of biology-anchored combinations because the development pathway isn’t as straightforward and the biology is clearly complex, but we will need to, because that is what the patient of the future will need in a decade.
What is your career advice?
Stay authentic to who you are, as much as possible. We can obviously strengthen certain tools in our toolbox or shore up weaknesses, but at the end of the day, focus on the work and the community that is there to support you, and spend less time trying to shape yourself into someone else’s mold.
Additionally, and particularly for women, don’t shrink yourself. Engaging in scientific or strategic debate, being a vocal contributor, and showing passion in the workplace are key aspects of what we do. However, there is a palpable concern that women who display those characteristics are viewed as difficult or aggressive, when sadly other adjectives like “passionate” would be used to describe similar behaviors from a man. There may be an instinct to shrink yourself to avoid this situation – but I encourage you to self-reflect here and ensure that you aren’t compromising yourself or your ability to impact.
What habits would you recommend young people do early on in their careers?
Find someone to look up to. The one thing that kept me motivated when things were tough was being able to look at other women in my organization to learn from. So many of us are willing to do that for others. Seeking out advice can only benefit you, so ensure you are networking and also learning from other’s journeys.
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