Haematologists are now deploying an attack strategy that has already stormed the beaches of solid tumour treatment paradigms by unleashing the patient’s own immune system with so-called “checkpoint inhibitors.”
As reported in two studies at the American Society of Hematology meeting in San Francisco, the anti-PD-1 checkpoint inhibitors from Bristol-Myers Squibb and Merck & Co – Opdivo (nivolumab) and Keytruda (pembrolizumab) respectively - have shown remarkable efficacy in classical Hodgkin lymphoma (cHL) patients who relapsed after failing all prior treatments.
“PD1 therapies target the immune system and enable it to respond to cancer as it is supposed to,” said Philippe Armand of the Dana-Farber Cancer Center and lead investigator for the nivolumab study.
A properly functioning immune system recognises foreign antigens and destroys the cells (usually pathogens) that display them; the same mechanism can, and often does work for attacking cancer cells. However, many tumour types are able to bypass this defence system by flipping the PD-1 switch on an attacking T-cell, and thereby induce a truce – the T-cells are on the frontlines, they’re well armed, but they do nothing.
Checkpoint inhibitors may be a perfect fit in certain types of cancer, and in particular cHL. “People have wondered for a long time how it was that cHL could attract such a brisk immune response and yet this response fails to kill the tumour,” said Dr Armand. “Genetic analyses showed amplification of genetic material on the ninth chromosome in these cells called 9p24.1, which leads to an increased expression of PD-1 ligands (PD-L1, PD-L2).” That turns the T-cells off.
Researchers hypothesised that the PD-1 checkpoint inhibitors would be the molecular bugle call that could send the immune system back into battle; they have already shown spectacular responses in melanoma. As a class, they have a fairly benign side effect profile, and most events are considered easily manageable.
In Dr Armand’s study, 105 relapsed or refractory cHL patients were treated. “These patients were heavily pretreated – 18 had already had failed a transplant and had few treatment options left.”
Results of the study showed that 20 patients achieved a partial, or complete remission, and the overall response rate was 87%. Importantly, as of this reporting, 48% of responses are ongoing. “Some of these patients have been in remission for over a year,” said Dr Armand.
A second, smaller trial for pembrolizumab (with 29 patients) reported very similar results in their cHL cohort.
'Amazing' results but...
Commenting on the results, Ronald Levy of Stanford University was impressed, but with a caveat. “These results are amazing – Phase I trials with immediate success.”
“However,” he continued, “the problem is that this is a disease that has a lot of cured patients already. How is this new drug type going to be integrated into the paradigm of treatment in Hodgkin’s disease?
“If it’s only used in relapsed or refractory patients that’s going to be of small use – how to move it up to front-line use in competition with all the other effective treatments we have…we shall see.”