Combining an Immune Checkpoint Antibody with an Anti-Angiogenesis Inhibitor

A small phase I study combining the immune checkpoint antibody ipilimumab with the angiogenesis inhibitor antibody bevacizumab showed promising results in advanced melanoma patients in 2011. Now, researchers are continuing to study the combination of immunotherapy and anti-angiogenic agents to understand which patients could best benefit from such a combination.

The 2011 study showed durable patient responses for over 6 months. These results were presented by F. Stephen Hodi, MD, Director of the Melanoma Center at Dana-Farber Cancer Institute (DFCI) /Brigham and Women’s Cancer Center, at the annual American Society of Clinical Oncology meeting that year.

Other trials are now underway to investigate the potential benefits of this combination. One phase I trial is looking at the anti-PD1 antibody nivolumab in combination with bevacizumab for non-small cell lung cancer.

Since 2011, Hodi and colleagues have been further exploring how the immunotherapy plus anti-angiogenesis combination could benefit patients. Their efforts included following up on the ipilimumab plus bevacizumab combination. At the American Association for Cancer Research (AACR) meeting this March, Hodi discussed the rationale for the anti-angiogenesis and immunotherapy pairing.

The researchers studied the tumor tissue of patients who had been treated with ipilumumab or another anti-CTLA-4 antibody to discover a hint of how this immunotherapy exerts its effects on the tumor. There seemed to be an important interaction between the immune system and the pathways that build and maintain blood vessels, adding to evidence from previous studies showing the direct interaction of white blood cells and angiogenesis pathways.

Hodi and another member of the DFCI, Glenn Dranoff, MD, observed that besides facilitating the infiltration of white blood cells called lymphocytes into the tumor, ipilimumab also appeared to cause the blood vessel network of the tumor to break down. Inhibition of VEGF has also been shown to affect whether immune cells can get into the tumor. Additionally, a patient who had a particularly long response to ipilumumab, lasting several years, had a particularly prominent number of anti-VEGF-A antibodies.

Tumors require a blood supply for growth, but because the making of new blood vessels requires a noninflammatory environment, tumors may suppress the immune response. This immune suppression is an advantage for the tumor in other ways also. “In essence, the tumors may take advantage of these mechanism of pro-angiogenesis and immune suppression to promote their growth,”  Hodi said.

In the phase I trial of ipilimumab plus bevacizumab, grade III toxicities included those that occur with bevacizumab therapy—protoneuria and hypertension. Ipilimumab-related grade III toxicities included two cases of colitis, uveitis, or inflammation of the eye, as well as hepatitis, all of which were resolved.

The kinetics of response to therapy tended to be drawn out —some patients had stable disease for 6 or more months before shrinkage of their tumors, including shrinkage of a metastatic liver tumor in one patient. Similar to what is known about treatment with a single immune-modulating agent, Hodi highlighted that traditional response measures of tumor shrinkage may not be the best way to understand whether a patient is deriving clinical benefit from this combination. This is because tumors treated with immunotherapy may be responding, but inflammation and other biological reactions within the tumor can make it appear to be increasing in volume.

Out of 46 patients in the trial, 18% had a partial response, meaning their tumor volume shrank by 30%. Fifty percent of patients had stable disease—no tumor shrinkage, but no further growth of their tumors. Because this was a dose-escalating trial, not all patients received the same dose of therapy. Those who received the maximum tolerated dose tended to have a better response: of the 17 patients treated at the maximum dose, 35% had either a partial or complete response and 53% had stable disease for at least 6 months. The trial had too few patients to demonstrate statistical significance of this response compared to patients who received lower doses of treatment.

“There is evidence that there are affects on the tumor immunity and the vasculature in this study,” Hodi said. Evidence includes changes in the types of immune cells identified in the blood of patients treated with the combination as well as changes in the pathology of the tumor after treatment, including changes in the tumor blood vessels. These correlative studies, along with the patient responses, show that there may be synergistic effects of a VEGF-blockade combined with an immune-checkpoint blockade.