Oncology
exists to protect. Immunotherapies have to tap into that power without making it toxic. In oncology, that means retraining the immune system to recognise, target and destroy cancer cells, while trying to keep the rest of the patient’s body out of the crossfire. It is a spectacularly difficult balance, but over the past decade, we have begun to see just what can be achieved if we get it right. “Cancer adapts, but so can the therapy,” stresses Wittrup. “If you can initiate a response that’s vigorous enough, the immune system will track subsequent variations in the cancer cells.”
Wrecking balls
He describes two general approaches. Firstly, by administering cytokines like IL2, which activate T-cells, doctors can manipulate “nature’s way of stepping on the gas”. The problem with naked IL2 infusions is that they don’t just direct the immune system to accelerate in the direction of cancer cells. Overstimulated T-cells screech into blind corners and pedestrianised zones all over the body, crashing almost indiscriminately into whatever crosses their paths. To avoid causing off-target damage, then, immunotherapies need to pay attention to the rules of the road. “The immune system is very orchestrated,” explains Wittrup, “it doesn’t turn on everything, everywhere, forever – it turns on certain things in certain places for certain times. And somehow, we just sort of entered into it as a community initially saying, well, let’s just soak the person in [cytokines] for as long as they can handle it. But that means you can't give them much because you just overactivated them, and it’s not how those very same molecules are used by the immune system.” We’re getting better at mimicking that. Patients receiving CAR T-cell therapies have their own immune cells extracted and tuned to target specific antigens on cancer cells. Unfortunately, at present they can only be used against very specific B cell cancers, as antigen targets on solid tumours and other types of leukaemia also appear on important healthy cells that can’t easily be replaced. Even in approved use cases, any cancer cells without the target antigen escape, increasing the risk of mutation and recurrence. “And with a therapy that’s as potent and effective as a CAR T-cell, there is a risk of toxicity,” warns physician-scientist David Scheinberg, head of Experimental Therapeutics at the Memorial Sloan Kettering Cancer Centre – “severe toxicity”. Copying one element of the immune system too closely can also subject therapies to the same pitfalls. Like their unaltered peers, expensively engineered CAR T-cells eventually stop killing cells with target antigens and shut down from exhaustion. This is a response to overactivation – another example of how the immune system limits itself. As Scheinberg points out, it’s a useful defence mechanism. “You don’t want your immune system to be overactivated all the time.”
Practical Patient Care /
www.practical-patient-care.com
Today’s best implemented immunotherapies take a different approach. In Wittrup’s terms, immune checkpoint inhibitors (ICIs) “take the brakes off” T-cells. They’re still liable to cause crashes – 66– 86% 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. About 20-30% of patients with metastatic melanomas treated with ICIs experience a complete response. Therapy can even be discontinued at that point, as the risk of relapse is estimated to be less than 10% over the following five years. Outside of immunotherapy, that’s unprecedented.
“Instead of just shifting the survival curve a little bit at the middle point, but ending up with everybody in the same unfortunate outcome, now the phrase is ‘raising the tail’,” explains Wittrup. “[Doctors and researchers] don’t like to use the word, but these people seem to be cured. So now the problem becomes, ‘How do we make that a larger number?’ As opposed to, ‘I have no idea what might work’, now it’s ‘we know this is working, how do we make it work all the time?’”. Without increasing the toxicity, that is. It’s much harder to justify potentially life-threatening adverse effects when treating less aggressive forms of cancer.
Toxic waste That’s where Wittrup and Scheinberg come in. Both are trying to build on the success of ICIs with immunotherapeutic techniques specifically designed to minimise toxicity. Wittrup calls it “spatio-temporal programming” – only giving the immune system the green light in specific circumstances. In his case, that
Immune checkpoint inhibitors block PD1 and PDL1 checkpoints that would otherwise fool T cells into thinking cancer cells are healthy.
15%
Close to this percentage of patients in the 1980s and early 1990s, treated with the early immunotherapy Interleuken 2 (IL2), saw their cancers go into remission.
FDA 33
Kateryna Kon/
Shutterstock.com
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