Oncology 66–86%
The majority of patients experience immune-related adverse events, which can strike almost anywhere in the body – but over the past decade, anti-PD1 and anti- CTLA-4 antibodies have started to change how
scientists think about tackling cancer.
10%
The risk of relapse in the five years after metastatic melanomas
therapy with ICIs is successfully discontinued
Nature Reviews
means anchoring cytokines in the tumour space. Scheinberg, meanwhile, is converting CAR T-cells into “micropharmacies”, which distribute lethal small- molecule drugs directly to cancer cells. That analogy is particularly useful for demonstrating how these approaches differ from the systemic way cancer drugs are usually delivered. Scheinberg’s ‘SEAKER’ (Synthetic Enzyme-Armed KillER) cells are directed to tumours by chimeric antigen receptors, but their primary mode of attacking cancers is by unmasking a separately infused small molecule prodrug called AMS, which was discovered by Derek Tan, chair of the Sloan Kettering Institute’s Chemical Biology Programme and Scheinberg’s collaborator for the project. Using specially engineered enzymes to activate highly cytotoxic molecules that the body can’t otherwise produce, these T-cells are able to destroy antigen-negative tumour cells and avoid the immune suppressing effects of the tumour microenvironment. The technology is being developed for human trials by CoImmune, which employs Scheinberg as a scientific advisor. Importantly, the T-cell-directed targeting system also confines the toxic effects of the small molecule drug, which is too poisonous to administer systemically, to the tumour space. Like a good pharmacy, SEAKER cells ensure that the correct doses of the correct medicines get to the right place at the right time. Scheinberg even jokes about sending in tiny pharmacists to process prescriptions – it’s spatio- temporal programming the way healthcare systems already do it.
“At some point, the physician or nurse would infuse the prodrug,” he explains, “so you can time when you want this to be active. It could be a week later or a month later or multiple times. And you can do it once or you can stop. It gives control over when this is happening, which is different than a [traditional] CAR T-cell, which is always on.”
“As an oncologist for 30 years, I've seen all the problems with the therapies. The drugs are extremely toxic. They’ve vastly improved, but we have a long way to go.” David A Scheinberg
That said, SEAKER T-cells that end up elsewhere in the body could also activate the prodrug, though Scheinberg notes that they haven’t caused notable toxicities in animal models. “The drugs, once made, are rapidly cleared out of the body anyway, so we think that the local accumulation at the tumour is what makes this effective without being toxic,” he explains. This is all still to be tested in human trials, but there’s a chance that the combinatory approach could also lower some of the toxicities associated with the current use
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of CAR T-cells. SEAKERs maintain their ability to activate prodrugs after their traditional immune functions have been exhausted, so the treatment may not require as many cells.
Cat and mouse Just as impressively, Wittrup’s team has found that cytokines specifically engineered to stay in one tumour can train T-cells to attack others elsewhere in mouse models. Using protein evolution techniques, they first created IL-2 and IL-12 molecules that stick like Velcro to collagen, the main component of the tumour microenvironment, and (with Darrell Irvine, associate director of MIT’s Koch Institute for Integrative Cancer Research) IL-12s that use the century-old vaccine adjuvant aluminium hydroxide to anchor themselves at their injection sites. In effect, they installed extra brakes on the cytokines before using them to step on the gas in T-cells. The two techniques (which have been licensed to Cullinan Oncology and Wittrup’s own Ankyra Therapeutics, respectively, and are expected to enter clinical trials in the next year) should work with most if not all interleukins, and, at least in mice, they appear to deliver systemic efficacy with localised toxicity. “There’s rapid communication among all the different immune cells in your body,” Wittrup explains. “The art going forward for us is to make sure that having generated this T-cell response, we support it sufficiently to get therapeutic effects systemically, but not so dramatically that we cross right back over to toxic territory.” The best way to do that? ICIs. “It doesn’t look terribly creative, because it is one of the best-selling drugs in the world, but anti-PD1 really works well to support those T cells when they leave the tumour.” As well as making the ‘step on the gas’ strategy viable, then, the work of Wittrup and his colleagues has the potential to make ICI therapies effective for more patients, without creating extra toxicities. In tests led by Wittrup’s former student Noor Momin, cytokines that bound to collagen were even found to enhance the effectiveness of CAR T-cells. The immune system is made up of interlocking, synergistic elements, so why shouldn’t immunotherapies be the same? “It’s a paradigm shift,” says Wittrup, connecting his work to the broader trend towards immunotherapy in oncology. “For so many years, the drug-makers’ job was defined as kill every cancer cell. That’s not it anymore. Now, it’s essentially to vaccinate. And you think about things differently if you’re making a vaccine.” It’s about working on the immune system’s own terms. That’s what drew Scheinberg to immunotherapy in the first place. “As an oncologist for 30 years, I’ve seen all the problems with the therapies. The drugs are extremely toxic. They’ve vastly improved, but we have a long way to go. And we’re hoping that this might be one further step in that evolution.”
Practical Patient Care /
www.practical-patient-care.com
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