Oncology round-up: CAR-T conference raises hopes for solid tumour therapy

Kisaco Research’s CAR-T Congress EU could not have come at a better time – the day after it finished NICE announced it had granted funding for a new use for Novartis’ cancer cell therapy Kymriah in lymphoma.

On Wednesday, the event's first day gave a fascinating technical insight into the latest developments in the field, with a UK-based team giving details of a CAR-T that offers hope in patients with solid tumours.

Delegates at the conference in London heard details from John Maher, clinical senior lecturer of immunology at King’s College, London, and chief scientific officer at Leucid Bio, who is leading the project.

The CAR-T targeting of a family of antigens known as ErbB is so powerful and reactive that Maher is only prepared to inject it directly into tumours to prevent reactions with healthy tissues.

Nevertheless after a phase I dose finding trial in head and neck cancer that began in 2015, Maher said the readouts so far suggest it could be used in combination with already approved checkpoint inhibitors.

By directly injecting the CAR-T into head and neck tumours Maher has been able to limit side effects in a phase I trial of 15 patients.

The best responders had stable disease (nine cases), and there is a suggestion from the results that it could improve survival – but further trials will be needed to explore this.

John Maher

Maher said of the efficacy trend that it was “provocative if nothing more than that”, adding that it could be added to platinum chemotherapy or a PD-1 inhibitor drug such as Merck & Co’s Keytruda (pembrolizumab), to improve its efficacy.

He also noted that there has been one long term survivor, who is in complete remission two and a half years after treatment after receiving a dose of Keytruda.

Manufacturing

The conference also heard how various biotechs are trying to refine or change the process for making cells that are capable of tackling blood cancer, and more challenging solid tumours.

Novartis has been struggling to meet demand for its approved CAR-T Kymriah (tisagenlecleucel), and has been looking to find ways to make manufacturing more efficient.

CAR-T (chimeric antigen receptor T-cell) therapies are manufactured by harvesting a patient’s own T-cells, genetically modifying them so that they target the disease, and then reintroducing them to the patient.

While the effects can be powerful, the challenges of producing the therapy in time is proving a challenge and the hunt is on to find new and faster ways to genetically engineer the CAR-T cells and get them to patients before their disease gets worse.

The genetic engineering step is proving to be a sticking point in the process, and there is a range of approaches being trialled that could be faster and more efficient than the virus-based gene editing used in approved CAR-Ts.

The conference heard from Michael Hudecek, director of the CAR-T Translational Research Programme at Universitatsklinikum Wurzburg, Germany who is working on cells that are genetically engineered using “sleeping beauty” DNA transfer.

This aims to be faster than the virus-based gene transfer but also prevents the risk of any virus left over from the process being left in the end product.

There have been no such issues in the approved drugs, but prior to approval in 2017 the FDA sought assurances from manufacturers that the process would not generate left-over retroviruses that could lead to new cancers.

“We need to make sure that no active viruses are presenting,” said Hudecek, whose technique is not based around viruses but a system based on “minicircles” of DNA that can be used to insert a piece of DNA code at 10% of the cost of a viral vector.

There was also a presentation from David Sourdive, executive vice president of technical operations at Cellectis, which is developing allogeneic “off-the-shelf” T-cell therapies in partnership with Servier and Allogene.

The gene editing system behind this technology is Cellectis’ system known as Talen – a class of proteins capable of inserting genes with high specificity and activity.

Is it working?

The side-effects associated with CAR-T are becoming notorious among patients too – and research showed that those who did not feel them after treatment became worried that the treatment was not working.

Alasdair Rankin, director of research and patient experience at the charity Bloodwise, gave a talk based on patient research conducted by the CAR-T firm Autolus.

The company is trialling a CAR-T therapy and gauged patients’ experience before, during, and after treatment, and found challenges at every step.

Rankin said that in many cases patients were not aware that they may not qualify for treatment – and understandably became angry when tests to double-check their eligibility came back negative.

Some thought these were just “baseline tests” and thought that inclusion on the trial was a “done deal”, he said.

Patients on the trial were also well aware of the fearsome side effects associated with CAR-T therapy – and were even using them to gauge whether the treatment was working.

Rankin said: “People very desperately wanted to feel that something was happening. People wanted to see some level of adverse events because it was an indication that something was going on.

“If they did not have that they would be worried it was not working.”

Members of the panel also noted the tremendous burden CAR-T therapy places on carers – Rankin compared the level of care at home needed with CAR-T to patients with conditions such as diabetes.

There were also worries in a debate about patient access that Brexit may affect reimbursement elsewhere in Europe.

NICE, along with the NHS and CAR-T manufacturers Gilead and Novartis, have managed to get the drugs reimbursed in England ahead of the rest of Europe.

But there are concerns that NICE’s dwindling influence after Brexit could hinder any dialogue with nations that have not reimbursed CAR-T yet, such as those in Eastern Europe.

And Anna Prokůpková, policy and project officer at the Association of European Cancer Leagues, added that nationalism on the continent is preventing use of any pan-European health technology assessment (HTA) that could be used to make CAR-Ts more accessible in countries in Eastern Europe.