For cancer patients with few other treatment options, the need for new targeted immunotherapies is genuinely a matter of life or death. So how to accelerate the development of new therapies? One key component is automated DNA synthesis. That was the take-home message from a recent GenomeWeb webinar featuring Stephen Schoenberger, a professor at the La Jolla Institute for Immunology, and Aaron Miller, an assistant professor at Moores Cancer Center at UC San Diego Health.
If you don’t have time to view the recording, here are some highlights from the presentations about creating new T cell receptor therapies with remarkable scale and speed. These T cell receptors are designed to recognize neoantigens, or subsets of mutations expressed in the tumor that provide excellent specificity for targeting only cancer cells.
Enabling new treatments
Schoenberger and his team are running trials in which they engineer autologous cells and restore them to patients as an adoptive therapy. Their goal is to make this part of the routine care available to cancer patients who have exhausted other treatment options. The idea is to have a series of off-the-shelf neoantigen therapies targeting commonly seen mutations, plus the ability to create new therapies based on private neoantigens as needed.
Functional testing of T cell receptors designed from tumor biopsy sequence data has remained a major bottleneck in the development of new neoantigen therapies, until now. In the conventional workflow, it would take about a month to clone the receptor into a lentiviral vector, test the constructs, and then evaluate its performance in a cell line. However, by implementing the BioXp™ system, the scientists have dramatically accelerated that process.
The BioXp™ system – an automated DNA synthesis and assembly platform – allows Schoenberger to clone as many as 32 T cell receptors in a single overnight batch and generate ten micrograms of DNA by the next morning. “This has really accelerated the pace and efficiency and dropped the cost of our TCR discovery platform,” he said in the webinar. Switching to a synthetic workflow eliminates the need to wait for slow bacterial systems and leads to cleaner results, he added. “It’s been absolutely transformative for us.” Productivity is at least 30-fold higher with the BioXp™ system, and project funding stretches to more candidates for testing.
Therapy in action
After Schoenberger described how the neoantigen therapy development occurs, Miller stepped in to offer a case study of how these personalized therapies can be used. The example he used came from a patient with pancreatic ductal adenocarcinoma that had a KRAS G12V mutation. The patient’s initial response to standard treatment was positive, but the cancer recurred. In-depth sequencing identified T cells specific to the KRAS mutation.
The BioXp™ system was deployed to help validate the specificity and effectiveness of the T cell receptor. Its use made it possible to develop the needed treatment and get it to the patient much faster than would have been possible otherwise. “We’ve been very pleased with the results that we’ve been able to achieve thus far,” Miller said.