PD-L1 expression is not the static, “yes/no” predictor of tumor response for which researchers hoped. Surface Oncology, Immutep and Corbus are each taking a different approach to immuno-oncology.
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Initially, anti-PD-1/anti-PD-L1 therapies offered the hope of curing cancer. Experience showed that despite truly amazing results in some patients and the approval of five such therapeutics in the United States and Europe, they elicited a response in less than one-third of those receiving them.
PD-L1 expression, while still an important biomarker, is not the static, “yes/no” predictor of tumor response for which researchers hoped.
The challenge for PD-1/PD-L1 checkpoint inhibitors is the tumor microenvironment (TME). It is such a complicated mass of cells and proteins that no single therapy is likely to cure all or even many types of cancers in all patients.
Now companies are pursuing other targets, often as adjuvants to moderate the TME and thus expand the efficacy of anti-PD-1/anti-PD-L1 therapies.
IL-27 and CD-39
Surface Oncology, for example, is in the clinic with programs against IL-27 and CD-39.
IL-27 is a cytokine that helps immune cells communicate with one another. It seems to be important in lung, liver and kidney cancer. Although it’s not present in most tumors, when it is there “it has a profound suppressive effect on both the innate and the adaptive immune system – the T cells and NK cells,” said Rob Ross, M.D., oncologist and CEO of Surface in an interview with BioSpace.
SRF388, a fully human anti-IL-27 antibody, breaks this cellular communication so the immune system can attack the tumor. Early indications suggest it can shrink tumors alone or in combination with pembrolizumab, an anti-PD-1 therapy.
Surface’s second program targets CD-39, an enzyme that is important in the adenosine axis, breaking down ATP, a metabolite inside healthy cells that acts as an immune stimulant.
“When ATP is found outside the cells, it means the cells have been broken apart,” Ross said, triggering the immune system to act.
“When ATP later is broken down into adenosine, that suppresses the immune system,” he continued. CD-39 is the protein that breaks-down ATP into AMP, which then is broken down into adenosine, Ross explained. “Cancer would love to be surrounded by adenosine, so the cancer cells up-regulate CD-39.”
Surface’s candidate, SRF617, inhibits CD-39, decreasing immune suppressions around the tumor.
Currently, SRF617 is a systemic technology, although more targeted delivery may emerge. “For the most part, if you have cancer, CD-39 is most active at the site of the tumor because you don’t have a lot of other areas of active inflammation,” Ross said.
“In the clinic, we’re pursuing both SRF388 and SRF617 in combination with anti-PD1 therapies,” he shared.
“What I expect is that in the future, patients with tumor types that respond to PD-1 at least sometimes will have combinations that combine anti-PD-1 therapies with drugs like ours,” Ross said. That will pave the way for more robust responses and, perhaps cures based upon turning on the immune system.
Leveraging LAG-3
In Australia, Immutep is developing eftilagimod alpha (dubbed ‘efti’) to modulate the lymphocyte activation gene-3 (LAG-3) immune control mechanism. Efti is a combination therapy with standard of care, currently in a trial for non-small cell lung cancer. A late-breaking abstract will be presented in November at the Society for Immunotherapy of Cancer (SITC) Annual Meeting.
“Efti works as an antigen-presenting cell (APC) activator. It’s not at all like checkpoint inhibitors,” said Marc Voigt, CEO of Immutep. “We use LAG-3 as a tool to activate the patient’s immune system via its ligand, MHC-II.”
Notably, Efti uses LAG-3 to activate both the innate and adaptive immune systems by binding to APCs like dendritic cells, monocytes and macrophages via MHC II molecules and leads to proliferation of CD4+ and CD8+ T cells.
“We are trying to induce a stronger immune response – especially the CD8+ cytotoxic immune response,” said Frédéric Triebel, M.D., Ph.D., CSO and CMO. There are a few approaches.
“For patients with a hot tumor and many activated T cells at the tumor site, you can block LAG-3 or PD-1, or block both together because the pre-existing T cells will continue proliferating. Or, with a cold tumor where there are few to no pre-existing T cells at the tumor site…you can induce T cells to go there with an APC activator such as efti,” Triebel said.
To do this, Immutep uses the immunostimulant efti to, in effect, form a new pathway that activates APCs such as the dendritic cells in the lymph nodes, skin, gut and tissues. These APCs present tumor peptides to the T cells and activate them so they can effectively recognize tumor cells and kill them. This approach can be combined with an anti-PD-1 therapy, such as pembrolizumab.
“In our clinical trials, we are not recruiting patients with high levels of PD-L1, which is a marker for T cell activation at the tumor site. Instead, we are recruiting all patients whether they have a hot or cold tumor,” Triebel said. “This expands the target population by more than three-fold.”
Targeting TGFß
At Corbus Pharmaceuticals, and throughout the industry, “We’re recognizing that the subtlety of the cell types in the TME drives responsiveness to PD-1 or PD-L1 therapy,” said Rachael Brake, Ph.D., CSO of Corbus Pharmaceuticals.
Cancer cells have multiple, pernicious ways to prevent the T cells from penetrating the TME. To thwart that, “Corbus is targeting a growth factor – TGFß – that is important in normal homeostasis but that is corrupted significantly in a large number of tumors,” she told BioSpace. When it’s allowed to signal, immunosuppression ensues.
Historically, targeting TGFß systemically hasn’t worked and, in fact, has created harmful target toxicities throughout the body.
“Corbus, therefore, is targeting cell-bound TGFß – which is tethered to the surface of the immune cells or the cancer cells, or to both,” Brake said.
The αvβ8 integrin is of specific interest. “It doesn’t appear to function like the other (20 to 30) members of this integrin family, and is the only integrin that exclusively functions as an activator of TGFß,” she continued.
Corbus’s lead compound, CRB-601, blocks the interaction between cell-bound TGFß and the αvβ8 integrin. Corbus plans to enter the clinic with CRB-601 in 2023, Brake shared.
