Scientists have uncovered a mechanism by which tumors can become resistant to treatment with checkpoint inhibitors including anti-programmed death-ligand 1 (PD-L1) and anti-programmed cell death protein 1 (PD-1) antibodies, and suggest one way of reversing that resistance, by blocking the cytokine transforming growth factor-β (TGF-β).

The discovery is based on findings from the 300-patient IMvigor210 biomarker study, the results from which led to FDA approval of the anti-PD-L1 antibody atezolizumab (Roche’s Tecentriq®) for the treatment of advanced bladder cancer. Data from the study, and from new tests in mouse models, are reported at the ESMO Immuno Oncology Congress 2017.

Checkpoint inhibitors, including atezolizumab, can generate durable anticancer responses in patients with a range of cancers, but they are not effective for all patients. “Understanding why the remaining 70% to 80% are resistant would enable us to target the mechanism with an additional drug and extend the benefits of checkpoint inhibitors to more patients,” suggests Sanjeev Mariathasan, Ph.D., senior scientist, oncology biomarker department, at Genentech, who is presenting the abstract “TGF-β Signalling Attenuates Tumour Response to PD-L1 Checkpoint Blockade by Contributing to Retention of T Cells in the Peritumoural Stroma.

The IMvigor210 study looked at both drivers of efficacy and resistance to atezolizumab, using methods that included immunohistochemistry, genome sequencing, and RNA expression. The results indicated that patients with the highest mutation burden, and tumors with T cells present in their microenvironments, were the most responsive to immunotherapy. In contrast, tumors with high TGF-β expression tended to be unresponsive to the antibody.

When the investigators looked more closely at what was causing treatment resistance, they found that there were three different types of tumor microenvironment. About 25% of cancers exhibited an “immune desert” tumor microenvironment, which was characterized by few T cells. Another 50% of tumors exhibited “T-cell-excluded tumors” in which T cells were stuck in the stromal microenvironment and did not penetrate the tumor. And about 25% of tumors were characterized as “T-cell-inflamed tumors,” in which the T cells did penetrate the tumors.

The studies indicated that T-cell-excluded tumors secrete a factor that constructs a collagen-rich “wall” around them, which makes the stromal microenvironment act as a sticky barrier that holds on to T cells and prevents them from getting into the tumor. Patients who were nonresponders to atezolizumab tended to express high levels of TGF-β expression and stromal genes induced by TGF-β in these excluded tumors, which Mariathasan and colleagues suggest may help to protect the tumor from T-cell attack.

The researchers next investigated whether inhibiting TGF-β could improve atezolizumab efficacy in a mouse model that exhibited the T-cell-excluded tumor phenotype. They found that in comparison with anti-PD-L1 antibody therapy alone, combination therapy using an anti-PD-L1 antibody and an anti-TGF-β agent reduced TGF-β activity in stromal cells and allowed the T cells to penetrate the tumor, leading to tumor shrinkage. “This suggests that giving anti-TGF-β and anti-PD-L1 together can remodel the stromal microenvironment and allow T cells into the tumor,” Mariathasan states. “The 'T-cell-excluded' phenotype is common in other cancers such as lung, pancreatic, and colorectal, so this combination therapy could be tested in a wider group.”

Ignacio Melero, M.D., Ph.D., senior researcher at the Centre for Applied Medical Research (CIMA) in Pamplona, Spain, notes that TGF-β is a soluble protein that has been shown to suppress immune responses through a range of mechanisms. “TGF-β has been pursued as a pharmacological target in cancer therapy research for some time,” he notes. “Inhibitors come in the form of neutralizing monoclonal antibodies and signaling inhibitors (SMAD inhibitors). These molecules are in clinical trials but have not yielded remarkable success because of efficacy and safety constraints. It is interesting to know that perhaps we can identify, by means of gene signatures, a fraction of patients in whom TGF-β is the dominant mechanism and focus on synergistic combinations blocking PD-1 and TGF-β simultaneously.”

Melero suggests that it would make sense to carry out a clinical trial combining anti-TGF-β therapy with a checkpoint inhibitor in bladder cancer patients with the telltale TGF-β signature. “Better anti-TGF-β agents need to be developed for use in combination with immunotherapy agents,” he notes.

George Coukos, M.D., Ph.D., Congress co-chair, professor and director, department of oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Switzerland, said that the results do help to explain why T cells are retained in the stroma and can’t move into the tumor. The findings also pave the way for developing combination therapies that improve the effectiveness of PD-1/PD-L1 inhibition. He suggests that trials should first be carried out in bladder cancer patients with the T-cell-excluded tumor phenotype, before moving on to testing the same approach against other tumors with the same phenotype. “The T-cell-excluded tumors are the low-hanging fruit in terms of clinical opportunity,” he states. “At the basic research level, we need to better understand why tumors establish this barrier to T-cell infiltration, how it is mediated, what role the stromal fibroblasts play, and how the immune-excluded phenotype gets orchestrated at the tumor site in order to escape immune recognition.”