I think a lot about the famous Arthur Clarke, that “any sufficiently advanced technology is indistinguishable from magic”. Of course one’s definition of ‘magic’ depends on vantage point, but surely I think this is a good way of thinking about the future. At the very least, it allows us to creatively imagine what would bring us what we want without technical or cost limitations. So what does magic look like in cancer therapy?
I’m imagining a world in which we track our health with precision and clinical accuracy. Before we even come into the hospital with symptoms, we should already be clued in that something is off by fitness trackers (heart rate, body temperature, glucose, HRV, blood pressure, metabolite trackers, etc.) and non-invasive daily diagnostics (smart toilets, retinal imagers, biomarkers from sweat, nose, ear, and mouth). Ideally, all this should happen routine in the background. No one should have to worry about this stuff constantly.
Let’s say we go to the doctor’s office, take a body scan and blood draw. A smear gets sent to pathology. From the blood draw, we are able to isolate the subset of cancerous cells, sequence them quickly and cheaply using a handheld Nanopore sequencer, run validated bioinformatic pipelines to determine differential tumor antigens and characteristics to exploit. Within the hour, we gather our care team of oncologists, pathologists, hematologists, and drug makers to develop a care plan for what we now know is early stage acute myeloid leukemia. Surely I don’t think the current slash, poison, burn paradigm is going anywhere anytime soon. But the rise of cell and gene therapies, biologics, and targeted small molecules has given us a large toolbox that we can be creative with.
We shoot for a complete remission in every patient and design a care strategy that leaves no stone unturned. From the patient’s perspective, all we are doing is giving an i.v. infusion, but what we gave is a carefully calibrated, personalized mixture of agents that attacks cancer cells in multiple orthogonal ways. Combination immunotherapies have become standard of care. With enough clinical experience and trials, we are able to get a strong guess as to which combination of agents will work, with minimal toxicity. For our AML patient, we decide on a demethylating agent like azacitidine plus a combination cell therapy cocktail. We wouldn’t want to do leukapheresis, but we are able to program NK cells and T cells in-vivo using targeted nanoparticles that deliver CAR constructs that are logic gated and ultra-sensitive to the multiple antigens that we discovered during sequencing. Importantly, these agents can all be dosed at custom doses and schedules. We can re-sequence the tumor and reformulate the nanoparticles whenever necessary, ideally this should all be plug and play.
Side effect management will be key in order to increase the therapeutic window for these drugs. This is an under-appreciated but vital part of the care process that gets overlooked. Here, I’m not only talking about anti-nausea drugs, pain killers, or steroids. Cancer patients should have access to top nutritionists to keep them energized, mental and physical health services, and access to green spaces, family visitors, and patient community groups. Cancer care should never stop at the bedside; basic health and food services are all part of the therapeutic process and can improve the performance of drugs.
Gradually with the help of real time monitoring of the patient’s cancer cell population, we are able to understand how this particular patient is responding to therapy and adjust as needed. Eventually as blood counts normalize, we want to ensure that immune memory is achieved and do one final sequencing run of blood samples. We want to make sure that when patients stop regular hospital visits, we leave them with an immune system that is capable of stopping relapses. With regular sequencing, we can even think about regular mRNA cancer vaccines if additional tumor antigens emerge.
I think one of the great things about science is that every researcher can dream and maybe eventually even see realized how their hard work fits into the patient picture. We each share a common goal of helping patients and each have our own narrative of how we aim to help. For me, I want to help scale cell therapy to the masses, making it more flexible, less expensive, and more tolerable to patients in need. Currently and for the past couple of years, I have been working on gene delivery using PBAE nanoparticles. The general idea is that these PBAE polymers are positively charged, and they form spherical polyplexes with negatively charged DNA, which are stable enough to be administered intravenously and delivery genetic payloads to cells in a dish or in vivo. One day when researching thesis ideas, I came across the idea of reprogramming T cells in-vivo to become CAR-T cells using the same PBAE delivery technology, published by the Stephan group at the Fred Hutch. This was pretty amazing for me because I then realized that as long as the delivery technology was good enough, we could theoretically make any genetic reprogramming based cell therapy happen directly inside the body. Of course I knew of the delivery challenges more broadly in gene therapy, and how better delivery would enable gene therapy. Enabling more flexible and more scalable gene therapy, cell therapy, and even potentially antibody therapy (reprogramming cells to produce antibodies), I began to realize that delivery technologies are a huge bottleneck for a huge pipeline of future therapeutic modalities, many of which seemed ‘magic’ to me.
An additional benefit of this research area for me was that it was inherently cross disciplinary and collaborative. I could work on the delivery technology while biologists would figure out exactly what gene construct would work, giving me exposure to cutting edge synthetic biology and pure bio/immunology research as well. Allowing the biology to play out concurrently has the added advantage of allowing me to concurrently observe the successes and failures of cell therapy clinical trials so that when the delivery technology is finally ready, some of the biological risk is mitigated. Last point I’ll make is that there are also a bunch of interesting companies working on delivery, some of my favorites including Generation Bio, Dyno Tx, Tidal Tx, and Sana. The business of biotech has always been interesting to me as well, and it’s very reassuring that the technology that I’m working on is relevant and commercializable. Overall, aside from the fascinating science and great opportunity to learn in a cross disciplinary environment, delivery seems to be the central challenge in translating cell and gene therapies, and eventually impacting patients, which is why we’re all here. Solving big problems and helping people in the process.
That being said, here are a couple ideas/topics I have been thinking about and wanting to work on within PBAE gene delivery:
Combination in vivo cell therapies enabled by targeted nanoparticles. Ie. what if we could reprogram T-cell, NK cells, macrophages with just a single nanoparticle mixture?
Developing a dictionary of highly efficient and targeted delivery vectors for each cell type, especially immune cells.
Developing systems of comparing different delivery vectors head to head.
Delivery of various types of payloads including DNA, mRNA, oRNA, siRNA, proteins, and other molecules.
Studying endocytosis and the biophysics of how nucleic acids are released and translated into proteins from nanocarriers.
Using microfluidic platforms to scale and systematize synthesis of nanocarriers.
Developing better (patient specific) in vitro models of transfection using organoid and lab on a chip platforms.
Improving targeting fidelity to tissues and cells of interest.
Improving targeting fidelity to the TME, and cancer cells in general.
Increasing packaging size for larger and more complex genetic payloads.
Co-delivery of multiple molecule types within the same particle
Modeling patient specific differences in drug delivery
Therapeutic projects for treating age related diseases and cancer
And of course like any other scientist, I have other side interests in:
Synthetic biology for materials discovery, information storage, and biomanufacturing
Discovery and characterization of new therapeutic modalities
Nucleic acid sequencing and writing technology
Cell sorting technologies
Genomic, transcriptomic, and epigenetic editing technologies
The biology of aging, cancer, and metabolism