The first lecture of the day was given by the expert in the area Elie Azoulay. He talked through immune therapies that are being used in cancer.
Immune therapy “boosts” the immune system and restores its ability to eradicate cancer cells. There are loads of different types of immune therapy – but Azoulay focussed on the ones that are of relevance to intensivists – Adoptive Cell Transfer, encapsulating “CAR T-cells” and “checkpoint inhibitors”.
Cancer cells normally find ways to act on checkpoints (molecules on T Cells) to avoid being attacked by the immune system. Checkpoint inhibitors, drugs like pembrolizumab and vivolumab [act on PD-1] or atezolizumab [acts on PD-L1] activate the immune system to get to work on tumours. BUT the usual safeguards against autoimmunity within the body are also affected. Other drugs that target CTLA-4 (such as ipilimumab used in melanoma) act as a type of “off switch” on T Cells. And they work in solid organ tumours – particularly in combination the oncology trial results are impressive… This paper is an overview of the field from a couple of years ago as quoted below:
There are lots of these drugs – how might you identify if your patient has received one? Well hopefully it will be abundantly clear from their treatment or oncologist – but they are all monclonal antibodies of course so end in -mab. Heres a list:
The other type of treatment in this category then is Chimeric Antigen Receptor T Cells (CAR-T cells). These are the patient’s own T Cells, apheresed, stimulated and expanded and then re-infused.
The treatments and trials of note are Tisagenlecuecel in the ELIANA trial for young people with refectory B Cell ALL and JULIET trial for high grade B Cell lymphoma and Axicabtagene cioleucel for relapsed B Cell lymphoma in the ZUMA-I trial.
The reason these second or third line cancer treatment matters for intensive care though is because of the serious adverse event rate. All this immune system jiggery pokery comes at the cost of upsetting normal function and some 30 to 40% of patients will get some sort of complication:
Toxicity in CAR T cell therapy (30 – 40%!)
— Jamie Strachan (@strachanjamie) October 1, 2019
So what will we need to do on ICU?
The lists of critical care support is quite long as theses patients can get multi organ failure requiring support! They range from ruling out infection (e.g. LP in neurotoxicity – is it CAR-T related or CNS infection/sepsis?) and admiting for close observation/monitoring, good symptom control/IV fluids through to oxygenation and ventilation for acute respiratory failure, vasopressors and shock treatment and even renal and cardiac support and monitoring. There are specific treatments – steroids are the mainstay but blocking the cytokines responsible for the cytokine storm (for example with IL6 antagonists / tacilizumab) and other rescue strategies.
Some of the complications are still not fully understood – for example neurotoxicity might be related to the parenchyma effect of CAR-T cells or might be a break down of the blood brain barrier, and earlier onset cytokine storm seems to lead to worse neurotoxicity – prompting some people to think there is a link. But its still an area of research…
The current reality in many units is that CART therapy is bringing patients to ICU for reversible pathology, and because CAR T therapy is an exciting area, perhaps perhaps it will expand beyond its current remit in cancer to other conditions… So we need to be ready!
My favourite bit of Azoulays talk today was his patient information leaflet – enjoy!