Side Effects Of Cancer Treatment Could Be Tempered By Intermittent Dosing
By Deborah Borfitz
June 9, 2022 | The frequency, degree, and speed of onset of immune-related adverse events from the experimental cancer drug AMG319, an inhibitor of phosphoinositide 3-kinase δ (PI3Kδ), came as an unwelcome surprise in a recent clinical trial involving patients in the UK with head and neck cancer. But the study also served to highlight how “absolutely critical” understanding of the immune system is to the development of rational immunotherapy, according to Christian H. Ottensmeier, M.D., Ph.D., a professor with the University of Liverpool and Clatterbridge Cancer Centre NHS Foundation Trust as well as an adjunct professor at La Jolla Institute for Immunology (LJI).
“We were trying to inhibit regulatory T cells [Tregs] with the aim to remove these cells preferentially out of the cancer,” says Ottensmeier. “We had not expected that the drug would also have such profound effects on the regulatory T cells in other tissues, such as the bowel. We were too successful in achieving the immunological goal we had set ourselves, and as a result had to close our study early.”
As reported recently in Nature (DOI: 10.1038/s41586-022-04685-2), 12 out of 21 patients treated in the placebo-controlled phase II neoadjuvant trial developed colitis, or inflammation in the colon, in just under a week. The researchers concluded that the immune system of the treatment-naïve cohort given AMG319 was “much more normal” than that of lymphoma patients in previous studies, upon which dosing in the latest study was based, Ottensmeier says.
“We thought that it would be best to use the starting dose [400 mg] that had been established as safe in people... [and] immunologically effective,” he continues. It also seemed unlikely that severe side effects would occur during the duration of the planned 24-day presurgical treatment with AMG319, since in lymphoma patients significant adverse events affecting the bowel and skin weren’t seen until after 40 to 60 days of treatment.
This underscores, “the fallacy of second-guessing what might happen in a different clinical setting,” says Ottensmeier. What the researchers had not predicted was that, unlike participants in their clinical trial, lymphoma patients in the earlier studies had previously undergone treatment and were therefore in an immunocompromised state going in.
The latest LJI-led study started off by using single-cell transcriptomics to analyze the tumors of patients, Ottensmeier says. After the study closed, single-cell transcriptomics was again used—this time in a mouse model—to interrogate what was happening to the cancer tissue. By the time the investigators realized they needed to amend the protocol to collect samples from patients with bowel abnormalities, the trial had effectively closed, so the tumor samples were all they had to scrutinize.
As desired, AMG319 was found to decrease the number of tumor-infiltrating Tregs, as well as cause modest clonal expansion of CD4+ and CD8+ T cells, says Ottensmeier. It was also associated with a significant increase in activated circulating Tregs.
The implication is that PI3Kδ inhibition either influences proliferation or displaces activated Treg cells from tissues, he says. “What we hadn’t expected was the cost to our patients in terms of side effects.”
Among the lessons learned are the importance of doing a careful and systematic evaluation of immune side effects, says Ottensmeier. “In the end, it is all the same immune system... [immunotherapies] are just doing slightly different jobs in different places.”
Additionally, the study points to needed vigilance about potential unintended biases when selecting treatment groups, he continues. The paired analysis of the same sample before and after treatment also proved to be “extraordinarily powerful in figuring out the immunological consequences [of treatment], in this case in the tumor and again when we looked at the bowel in the mouse.”
In mouse models, when AMG319 was given intermittently it sustained anti-tumor immunity and curbed the side effects. So, the team between LJI and the University of Liverpool is now in the protocol design stage with another clinical study that will investigate intermittent dosing in hopes of achieving sustained anti-tumor immunity with reduced toxicity, Ottensmeier says. The intent is to find a partner who will provide the PI3Kδ inhibitor, perhaps in combination with an anti-PD-1 monoclonal antibody.
Although the original discontinued study focused on head and neck cancer, it unexpectedly also opened the door to better understanding of inflammatory bowel disease, he adds. Therapeutic strategies based on removing Tregs, unless able to do this selectively in the cancer tissue, can be predicted to cause the same debilitating side effects.
To that end, a careful reading of the Nature paper might potentially prevent toxicities from other compounds that drive the removal of Tregs, says Ottensmeier, noting that their activation is typically the same in both the tumor and healthy structures in the body.
Interestingly, in anti-PD-1 treated patients, only a very small minority of patients get colitis, Ottensmeier says. “Our data would propose that the colitis that comes from removing regulatory T cells might be biologically distinct from the colitis that comes from T cell activation.”
In the newly published paper, a subset of T regulatory cells recognized as important in pathogen defense in the colon was blocked by AMG319, says Ottensmeier. Without Tregs on the job, pathogenic T helper 17 (Th17) and type 17 CD8+ T cells moved in and caused inflammation and colitis.
It will be important to disentangle whether these Th17 T cells have the job to protect the body against infection, he continues. “If that is the case under normal circumstances, then we would expect that removing the brakes on these cells would cause inflammation.”
It is also not well understood how the immune responses against microbes might be linked to immune responses against cancer, says Ottensmeier. “However, we do know that altering the microbiome in the bowel with antibiotics can have adverse effects on the benefits from immunotherapy. Removing regulatory cells in the bowel activates what I presume to be an antimicrobial responses.”
Answers will require a closer look at the microbiome also in the skin, mouth, and the lung, he adds. “Normally we are sort of in balance with the bugs that live on us and in us. But if we were to release the immune cells that manage these bugs it might trigger immune-related effects... because we’ve meddled with our [epithelial] barriers.”