1. DiGiulio, Sarah

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When it comes to a tough problem to solve, two heads are better than one. And when it comes to fighting cancer, two anticancer immunotherapy drugs might be better than one, too.

Sarah Buchan, PhD. S... - Click to enlarge in new windowSarah Buchan, PhD. Sarah Buchan, PhD

A recent preclinical trial in mice found that combining antibodies that target PD-1/PD-L1 with an antibody targeting CD27 dramatically improved the effectiveness of the drugs against cancer cells. The results published online ahead of print in the journal Clinical Cancer Research showed that the combination of drugs was six times as effective at preventing cancer cell growth in multiple tumor models of melanoma and lymphoma than either of the drugs alone (2018; doi:10.1158/1078-0432.CCR-17-3057).


"Blocking PD-1, or its major ligand PD-L1, has been a game changer in oncology and has prolonged patient survival in difficult to treat cancer types," study author Sarah Buchan, PhD, a senior post-doctoral research fellow at University of Southampton in the U.K., told Oncology Times. "However, only a minority of patients respond, suggesting that combining PD-1/L1 blockade with another approach may be of benefit." PD-1/PD-L1 antibodies currently are given to people with melanoma, lung cancer, and other cancers.


The researchers initially compared the activity of several agonist antibodies targeting co-stimulatory receptors and found that anti-CD27 was the most effective at increasing T cells-which is why they went on to test the anti-CD27 immunotherapy with the PD-1/PD-L1 blockade, Buchan explained.


The new data is early, as it was done in animal models, not people, but it supports further clinical trials in patients to test the effectiveness of this immunotherapy combination. In an interview, Buchan elaborated on how this initial work was done and why the findings are significant.


1 You didn't pick this drug combination at random. Can you explain what led you to test this combination of immunotherapies?

"Anti-PD-1/L1 exerts its effect by releasing the brakes on T cells that are otherwise rendered ineffectual in a tumor environment. However, a large body of evidence, including from [Aymen Al-Shamkhani, PhD, Professor in Immunology at Southampton, and his group], shows that T cells require co-stimulation to maximally respond to infections and tumors. Thus combining PD-1/L1 blockade with a driver of T-cell co-stimulation such as an agonist antibody targeting CD27 seemed a logical approach.


"We have reported previously that anti-CD27 and PD-1/L1 blockade can restore functions to T cells that have become 'exhausted' due to prolonged activation in mice (J Immunol 2015;194:125-133). However, we had not tested whether this combination would be similarly effective for increasing anti-tumor immunity. The present paper describes that this is the case across several tumor models and provides mechanistic insight into how these two agents might be acting on T cells."


2 It has been noted that this new data suggests this drug combination is ready to be tested in clinical trials in patients. What types of cancers do you suspect the immunotherapies will be most effective against?

"PD-1/L1 blockade has proven successful in a broad range of tumor types and we will have to see if this proves to be the case for anti-CD27 (known as varlilumab in the clinic). Currently the combination of varlilumab and nivolumab (anti-PD-1) is being [tested in clinical trials] (NCT02335918) in patients with a range of cancer types: squamous cell carcinoma of the head and neck, ovarian carcinoma, colorectal carcinoma, renal cell carcinoma, and glioblastoma.


"Evidence from the existing literature suggests those tumors that have a higher frequency of T cells at the start of therapy respond better to treatment with PD-1 blockade, so this may be a factor which will similarly influence the efficacy of varlilumab."


3 Does the success of this combination of drugs suggest that other immunotherapy combinations might be effective? What's the takeaway about new drug combinations and their potential?

"It seems likely that PD-1/L1 blockade will similarly combine with other T-cell co-stimulators to improve tumor therapy, and there is some evidence from mouse models that this is indeed the case. However, more research is needed to determine the effects of these combinations on distinct T-cell subsets and in human disease where the tumor environment is less homogeneous than in mice.


"Understanding the local environment of a given patient's tumor is going to be key in determining the most effective treatment. We already know that responders to anti-PD-1 tend to be patients who have a pre-existing T-cell population in the tumor, and in which the tumor cells express PD-L1.


"Going forward, it may be necessary to have a more sophisticated understanding of the immunological milieu that exists in different tumor types and within the same tumor type at different stages of disease in order to provide appropriate immunotherapy regimens."