Improving the success rates of immunotherapy drugs has long been a difficult challenge. But finding ways to accurately measure the presence of CD8+ T cells could provide more certainty, according to pioneering US biotech ImaginAb
It’s more than a decade since the first checkpoint inhibitor came to market, which was a turning point in cancer immunotherapy. And although these drugs — such as PD-1 inhibitors — proved to be highly effective in some cases, response rates have always been an issue.
There have also been several shocking trial failures when drugs that produced convincing results in early phase trials or in one tumour type failed to produce significant efficacy in later stage trials or other tumour types.
Since then, oncologists have been trying to find ways to improve response rates and predict which tumours are most likely to respond to immunotherapy. Checkpoint inhibitors work by flipping a biochemical switch that makes tumours visible to the immune system, calling in an attack from T cells.
T cells expressing the CD8 receptor (CD8+), often called cytotoxic T lymphocytes, are instrumental in the immune system’s response to cancer and their presence within tumours has proven to be a strong predictor of whether these therapies will succeed.
But measuring the presence of CD8+ cells is difficult and, for the most part, clinical trials are reliant on blood sampling and biopsies to measure its presence.
However, there are known limitations to biopsies such as their invasive nature, sampling error and problematic repeatability. Sampling CD8+ cells can give extensive information about their phenotype but does not provide the crucial insight about whether they are able to enter a tumour (where they can have a therapeutic effect).
ImaginAb has designed a product to measure the presence of CD8+ T cells in and around tumours by labelling them with a radioactive antibody fragment, allowing them to be imaged using a PET scanner.
The company’s investigational technology is called CD8 ImmunoPET (89Zr crefmirlimab berdoxam), an 89Zr-labelled “minibody” that’s designed to bind to the CD8 receptor on human T cells. This allows for non-invasive imaging and is being developed as a way to determine the immune status of a patient and the potential efficacy of immunotherapies.
ImaginAb CEO Ian Wilson (pictured) notes that the location and number of CD8+ T cells in and around tumours is an indication of whether they are navigating to the right sites, infiltrating the tumours and likely to shrink it with time.
He said: “Our ongoing Phase II clinical studies seek to demonstrate a correlation between CD8 presence in tumours and patient response to immunotherapy.”
“In our Phase IIa iCORRELATE study, we showed for the first time that we can measure this response in every tumour lesion with CD8 ImmunoPET. With whole-body CD8 images, any type of cancer targeted by immunotherapy can be visualised and measured against CD8 number throughout the rest of the body.”
“In addition to visualising CD8+ cells within tumours, the technology also allows us to see normal immune organs such as the spleen, lymph nodes and bone marrow. Increases in CD8+ T cells in all tissues, before and during treatment, may provide early evidence of drug pharmacodynamic response; the activation of lymph nodes is a common observance.”
CD8+ cell imaging may also address a variety of challenges in the cancer drug development process, such as the confirmation or determination of mechanism of action. CD8+ cell profiling could also aid with prioritising indications/tumour types based on the CD8 cell response, determining optimal dose and finding immune-related serious adverse events.
According to Wilson, the technology could be used in a predictive manner to profile whether combination therapies could be suitable for certain tumours. He added: “Drug developers can use baseline and on-treatment CD8 ImmunoPET images to visualise patients with and without combination drugs to see differences in CD8+ cell influx.”
“For example, CD8 ImmunoPET may be used to determine if a novel drug candidate has enough horsepower to be used as a single agent, of if it should be combined with other therapies — such as standard of care check-point inhibitors — for a more powerful effect on the activation of the immune system. Likewise, using CD8 ImmunoPET imaging may help to decide which drug to administer first, based on increasing CD8+ T cell numbers via expansion or trafficking.”
ImaginAb has conducted its own research to show that pharma and biotech firms are waking up to the potential of CD8. A survey of 15 active immune-oncology pharma companies in May 2022, and a follow-on survey of 44 biotechs in November 2022, revealed that 93% of pharma and biotech companies are currently measuring CD8+ T cells in tumours in their clinical studies.
Furthermore, 86% of respondents consider this measurement to be important in terms of decision making.
The 93% majority measuring CD8 in tumours are currently using multiple methods to provide complementary data such as IHC, flow cytometry or RNA/genomic methods.
The follow-on survey revealed that 80% of respondents are currently primarily measuring CD8+ T cells in tumours for immunomodulators, T-Cell engagers and vaccines. Of the remaining 20% who are not currently measuring CD8 cells, half expect to start doing so within the next 3 years.
According to Wilson, the future direction of CD8+ T cell research involves technical details about the baseline levels of CD8 infiltration required to induce a response with checkpoint inhibitors. Ongoing studies are being done to determine the change needed from baseline that is predictive of tumour and patient response once therapy has begun.
Wilson concluded: “Once these details become clear, it may be much easier and faster to identify patients that are likely to respond to immunotherapy before starting treatment and/or identify patients that are responding faster than current methods. With this information, clinicians should be able to provide more effective and more personalised care.”