A decade ago, oncologists had little to offer most patients with metastatic renal cell carcinoma (RCC). However, a breakthrough discovery that has already changed the treatment of metastatic melanoma is showing promise against other metastatic cancers—including metastatic RCC—and giving patients new hope for long-term survival.
The breakthrough was the discovery of cytotoxic T lymphocyte antigen 4 (CTLA-4), a receptor on the surface of T cells that blocks the immune response by inhibiting T cell activation. James Allison, Ph.D., then a professor at the University of California, Berkeley, and now a professor in and chair of the Department of Immunology at The University of Texas MD Anderson Cancer Center, developed an antibody, anti–CTLA-4, that blocks this “immune checkpoint” protein, freeing the immune system to attack and inactivate tumors. Dr. Allison and his team discovered that blocking the CTLA-4 pathway caused tumor regression.
In clinical trials, anti–CTLA-4 (now known as ipilimumab) significantly extended survival in patients with advanced melanoma, and the approval of ipilimumab by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of metastatic melanoma was a game-changing development. Many oncologists have now turned their attention to the use of immune checkpoint inhibitors against other types of cancer.
Immunotherapy in advanced RCC
One cancer in which the new immunotherapy approach is generating excitement is metastatic RCC. Conventional therapies typically have little effect on survival in patients with metastatic RCC. While this began to change in the past decade with the introduction of targeted agents such as vascular endothelial growth factor pathway or mammalian target of rapamycin inhibitors, these agents are effective only in subsets of patients. An alternative is needed for patients who do not benefit from these therapies.
“Immunotherapy has been around a very long time,” said Padmanee Sharma, M.D., an associate professor in the Department of Genitourinary Medical Oncology. “Cancer researchers have grappled for decades with how to harness the body’s innate immune system to fight tumors. The early studies focused on how to turn the immune system on.” She said these studies led to the treatment of advanced RCC with high doses of cytokines such as interleukin-2 and interferon, which promote T cell proliferation. Although the high-dose cytokine treatment has been available for more than 20 years, only a small portion of patients with metastatic RCC are candidates.
“For years, many permutations of this ‘on switch’ approach have been tried without major success because the complexity of the immune system was not well understood,” Dr. Sharma said. “Dr. Allison’s work showed that turning the immune system on isn’t enough because once turned on, the immune system is programmed to turn itself off. Only by overriding the ‘off switch’ can we get an antitumor effect, and that’s what the checkpoint inhibitors do.”
Nizar Tannir, M.D., an associate professor in and deputy chair of the Department of Genitourinary Medical Oncology, likened the effect of the checkpoint inhibitors to “releasing the brakes” on the immune system, allowing the T cells to attack cancer cells.
After the discovery of CTLA-4 and its inhibitor, Dr. Tannir said “the whole field just broke open” as substantial efforts were made to develop inhibitors of other checkpoint proteins. Nivolumab—an inhibitor of another checkpoint protein, programmed cell death protein 1 (PD-1)—is now in phase III clinical trials at MD Anderson and elsewhere for the treatment of metastatic RCC and other cancers. Dr. Tannir said, “We now have a whole new class of drugs targeting these checkpoint proteins, and the excitement is building. We’re seeing remarkable responses.”
The success of checkpoint inhibitors has generated a great deal of public interest. “Patients are very much aware of the effectiveness of these agents and are eager to enroll in an immunotherapy trial,” Dr. Sharma said. “They don’t want to wait for FDA approval; the earlier they can get the treatment, the better.”
Drs. Sharma and Tannir said that they expect new trials of checkpoint inhibitors for treating RCC and other cancers to be opening soon and that they anticipate FDA approval of nivolumab for the treatment of advanced RCC in the near future.
High expectations for combination regimens
While the checkpoint inhibitors tested thus far have yielded some remarkable results, the drugs are not effective in all patients. Attempts at improving response rates led naturally to combinations of more than one checkpoint inhibitor. Various combinations of CTLA-4 and PD-1 inhibitors are now in phase I and II clinical trials for treating various cancers.
Although study results of combinations of checkpoint inhibitors for the treatment of metastatic RCC are not yet available, an early trial of one such combination for the treatment of advanced melanoma yielded a 1-year overall survival rate near 80%, which was previously unheard of for agents used to treat advanced melanoma. Drs. Tannir and Sharma anticipate equally outstanding results in patients with RCC.
Checkpoint inhibitors are also being combined with targeted agents such as sorafenib and sunitinib for treating metastatic RCC. While the results of these trials are not yet available, the combination approach is expected to have a big impact on the survival of patients with advanced cancer.
Checkpoint inhibitors unlike conventional therapies
One of the most exciting aspects of checkpoint inhibition in cancer therapy is that, unlike conventional cytotoxic drugs and targeted agents, it has the potential to work universally in all cancers. Checkpoint inhibitors, alone or in combination, have yielded promising results not only in advanced melanoma and RCC but also in triple-negative breast cancer and cancers of the prostate, bladder, lung, and head and neck.
Dr. Sharma said, “Checkpoint inhibition works in many different tumor types because it doesn’t target specific tumor cells, which can vary dramatically from patient to patient. Rather it targets the immune system, which is essentially the same in everyone. We all have T cells, and all T cells have CTLA-4 and other checkpoint proteins—and that’s why blocking the checkpoints can work in so many different kinds of cancer.”
The checkpoint inhibitors also differ from conventional therapies in their side effects. Dr. Sharma explained, “We see inflammatory effects—uveitis, dermatitis, colitis, hepatitis, pancreatitis—all due to the continued activation of the immune response. These immune-related adverse events can be controlled very well with corticosteroids as long as they are caught early and treated promptly. Most of these effects are readily reversible.”
One side effect of checkpoint inhibitors that is not reversible is hypophysitis, affecting the pituitary gland. The few patients who develop this adverse effect require long-term treatment with a low-dose oral steroid.
Surprisingly, steroid treatments for immune-related adverse events do not seem to substantially reduce the checkpoint inhibitors’ antitumor effects. Dr. Sharma said, “We don’t fully understand this yet. We believe it’s because the patient has had the chance to build a considerable immune response before starting the steroid treatment. The patient has enough intact memory B and T cells to mount the antitumor response while the steroid suppresses the newer, developing immune cells. We’re still learning about the pathways regulating these responses.”
Duration of therapy is another way checkpoint inhibitors differ from other systemic therapies. In the early clinical trials of ipilimumab, investigators noticed that patients who stopped treatment early, sometimes after only a few doses, still had dramatically prolonged survival. Eventually the researchers determined that only four treatments over 12 weeks would confer the therapy’s survival benefit, and this is now the standard, approved regimen. While it is too early yet to tell whether nivolumab and other checkpoint inhibitors will show similar survival benefits with such a brief treatment period, Drs. Sharma and Tannir believe the new drugs will follow the same pattern as ipilimumab.
A final way that checkpoint inhibition differs from other therapeutic approaches is in how success is defined. While responses to conventional therapies are measured by imaging studies or laboratory tests, response to checkpoint inhibitors is typically measured by survival benefit. “We have patients with metastatic melanoma who have survived for nearly 10 years since starting checkpoint inhibition therapy in a phase I clinical trial,” Dr. Tannir said. “And patients with advanced RCC have survived 2 or 3 years—or even longer—since beginning treatment with a checkpoint inhibitor. They’re alive and they’re doing well, but we can’t call their responses complete. Many of these patients have abnormalities on computed tomography that may be residual tumor. We’ll never know for sure because the disease has been stable so long, and the patient has been living so long, that it doesn’t really matter. These are patients who a decade ago wouldn’t have been expected to live 1 year.”
Future looks bright
Following the success of checkpoint inhibitors in patients for whom other therapies had failed, some current trials are looking at the drugs’ efficacy in treatment-naïve patients with metastatic RCC or other cancers. Dr. Tannir said, “There is enough confidence and excitement about the efficacy of these drugs to say yes, we can put them up front: we don’t necessarily have to try a targeted agent, such as a tyrosine kinase inhibitor, as a first-line therapy. We can go right to the checkpoint inhibitor.”
Drs. Tannir and Sharma anticipate that checkpoint inhibition will be one of the dominant paradigms in cancer research over the next several years, as investigators try various combinations and regimens to determine the optimal treatment for specific patient populations.
In this era of genomic medicine, predicting which patients will respond to a specific agent or combination of agents or modalities has become feasible. “But, given the complexity of the immune system,” Dr. Sharma said, “a single predictive biomarker is probably not going to determine patient response. Rather than selecting a subgroup of patients who are the ideal candidates for immunotherapy, we will think about how each and every patient could benefit from immunotherapy. Our objective will be to modulate each patient’s immune response with an appropriate agent or combination to optimize the antitumor effect. The point is not to exclude patients, but to get each patient’s immune system to function the way the immune systems of responders are functioning.”
The clinical trials now under way should set the direction for future treatment refinements. “The combination regimens are so promising—they offer endless opportunities to alter dose and schedule and synergistic effects to invoke a powerful antitumor immune response in every patient,” Dr. Sharma said. “Immunotherapy is different than other therapies. It’s a paradigm shift, a culture change. We are beginning to elicit its true potential.”
For more information, contact Dr. Padmanee Sharma at 713-792-2830 or Dr. Nizar Tannir at 713-563-7265.
OncoLog, August 2014, Volume 59, Issue 8
In July 2012, Philip Prichard underwent a right nephrectomy for renal cell carcinoma (RCC), which was found to be clear-cell RCC with greater than 90% sarcomatoid elements. The cancer recurred 5 months later as a large tumor in the right nephrectomy bed that invaded the liver and was deemed unresectable.
Despite treatment with the targeted agent pazopanib, the disease progressed within 16 weeks. In March 2013, Mr. Prichard was referred to MD Anderson, where Nizar Tannir, M.D., and other clinicians enrolled him in a clinical study of the intravenous (IV) anti–PD-1 antibody nivolumab.
Mr. Prichard described a typical visit: “Every 2 weeks, I get up at 4 a.m. and fly to Houston. I get here, they draw blood, and I see Dr. Tannir. Then I get hooked up to an IV and sit there about an hour. Unless they need to do scans, I fly home the same day.”
Mr. Prichard said that when he first came to Houston, he was anemic and suffered from pain, drenching night sweats, and fatigue. “I could barely walk through the airport,” he said.
Within 8 weeks of starting treatment, his energy had returned and he was feeling better. Dr. Tannir said the tumor was also responding to the treatment and had shrunk to half its former size in the first 8 weeks of treatment.
After 13 months of treatment with nivolumab, 75% of the tumor was gone, and Mr. Prichard had experienced no adverse events. Describing the response as near complete, Dr. Tannir said, “His anemia has resolved, and he has energy. He’s healthy again.”
Mr. Prichard said he is back at work and is active again. “It’s been life-changing,” he said.