New England Journal of Medicine publishes two papers
that could help improve and extend current treatments
August 5, 2016 – Immunotherapy and precision treatment are two of the biggest trends in cancer research and treatment today. Studies published recently in the prestigious New England Journal of Medicine show that SU2C-supported researchers are at the forefront of these remarkable trends. These studies deal with immunotherapy in advanced melanoma and targeted therapy in metastatic prostate cancer.

Overcoming resistance to immunotherapy

Therapies involving the body’s immune system to fight tumors have been one of the big breakthroughs in cancer treatment in the last few years. Many patients with advanced melanoma have seen their tumors shrink or virtually disappear after treatment with pembrolizumab (Keytruda); 40 percent of patients in one major study (KEYNOTE-001) survived at least three years. Since the five-year survival rate in metastatic melanoma has been only 4 percent, this is a huge change.

However, some patients who respond initially then experience renewed growth of their tumors. Scientists want to know why this happens so they can seek ways to overcome this type of resistance.

With SU2C support, Antoni Ribas, MD, PhD, professor of medicine and director of the tumor immunology program at the UCLA Jonsson Comprehensive Cancer Center, and Jesse Zaretsky, a doctoral student in Ribas’s lab, conducted a study of “immune escape” in advanced melanoma. They focused on patients who had experienced regression of their tumors after treatment with pembrolizumab, but then relapsed and experienced progression of the disease. This happens to about one in four of patients who initially respond to drugs like pembrolizumab.

Pembrolizumab is an antibody that fights cancer by restoring the function of the immune system’s T cells so they can attack cancer cells. It works by blocking a path between the T cells and the cancer cells that otherwise acts as a checkpoint and “turns off” the T cell’s natural ability to attack the cancer. Nivolumab (Opdivo), which was not used in this study, is another drug that works in a similar manner. This treatment approach, known as checkpoint inhibition, has shown success in melanoma, Hodgkin’s lymphoma, and lung and renal cancers.

“The tremendous promise of immunotherapy is to engage our body’s immune defenses to fight cancer, but the results must be long-lasting,” Ribas said. “We have now identified for the first time mechanisms that cancer cells can use to avoid recognition by the immune system’s T cells and decrease sensitivity to their attack.”

Ribas and Zaretsky discovered specific changes in the genetic makeup of tumors when comparing biopsies taken before treatment with those taken after resistance had set in. Finding these genetic mechanisms that may account for the eventual failure of the treatment potentially opens a path to treating relapsed disease or avoiding it in the first place by modifying current immunotherapies or developing new treatments. Their results were published in the New England Journal of Medicine on July 13, 2016.

Precision treatment and targeted therapies

Meanwhile, researchers in the United States and United Kingdom supported by SU2C reported that men with metastatic prostate cancer were more likely to have certain types of variations (mutations) in their DNA than men whose prostate cancer is localized. Based on this, the researchers suggest that men with metastatic cancer should have their DNA sequenced to see if they are candidates for targeted therapies, especially for drugs known as PARP inhibitors. These are drugs that attack the processes that help cancer cells repair damage to their DNA, leading to death of the cancer cells.

“Our study has shown that a significant proportion of men with advanced prostate cancer are born with DNA repair mutations – and this could have important implications for patients,” said Johann de Bono, MD, PhD, professor of experimental cancer medicine at The Institute of Cancer Research in London, who led the study in the U.K.  “Genetic testing for these mutations could identify men with advanced prostate cancer who may benefit from precision treatment. We could offer these men drugs such as PARP inhibitors, which are effective in patients with certain DNA repair mutations and are showing important anti-tumor activity in ongoing clinical trials.”

Finding DNA repair mutations in a male patient with prostate cancer can also have implications for both male and female relatives of the patient. The men in this study had so-called “germline” mutations, meaning that they were present all along, either inherited from another family member or developed before birth, giving a high likelihood that the mutations may be present in other family members.

The researchers are suggesting that all men with metastatic prostate cancer should consider being tested for inherited mutations.

“Where we find BRCA2 mutations, we could also offer genetic testing and counseling to relatives of the patient to consider how we can reduce their cancer risk,” de Bono said. “We also need to establish the impact of having DNA repair defects on survival in men with prostate cancer, and whether we can predict who will develop severe disease, so we can design new treatment strategies to cure this disease.” The paper was published in the New England Journal of Medicine on July 6, 2016.

SU2C’s Impact

While immunotherapy is bringing lasting remission in many patients, others do not benefit at all, or benefit but then relapse. Studies like the one conducted by Ribas and Zaretsky are critical to figuring out how to extend the benefit of immunotherapy to more patients on a longer-lasting basis.

The same is true with precision medicine. Careful studies are needed to identify patients who are more likely to benefit from particular therapies, thereby avoiding lost time and ineffective treatments. And understanding the genetic make-up of patients’ tumors can help not only with treatment but with screening and prevention.

The study by Ribas, Zaretsky (who is participating in the UCLA-Caltech Medical Scientists Training Program), and colleagues was supported by the SU2C-Cancer Research Institute grant to the SU2C-Cancer Research Institute Cancer Immunology Dream Team.

The study by de Bono and colleagues was supported by the grant to the SU2C-Prostate Cancer Foundation Prostate Cancer Dream Team.

For Further Reading

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma, by Jesse M. Zaretsky, BS, Antoni Ribas, MD, PhD, et al., New England Journal of Medicine, July 13, 2016 http://www.nejm.org/doi/full/10.1056/NEJMoa1604958 (Free download)

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer, by Colin C. Pritchard, MD, PhD, Joaquin Mateo, MD, Johann de Bono, MD, PhD, et al., New England Journal of Medicine, July 6, 2016. http://www.nejm.org/doi/full/10.1056/NEJMoa1603144 (Free download)

AACR August 4, 2016