Novel drug combination shows promise in treating advanced skin cancer in kidney transplant recipients

People who have had a kidney transplant have an increased risk of developing skin cancer. A new study led by researchers at the Johns Hopkins Kimmel Cancer Center is exploring the best combination of treatments to target skin cancer while preserving transplanted organs.

Now, they’ve launched a new drug combination designed to stimulate the immune system to fight potentially deadly advanced skin cancer without permanently damaging a patient’s transplanted kidney. We report the results of a clinical trial testing the This treatment involves two types of immunosuppressive drugs to protect the transplanted kidney and one or two types of antibodies known as checkpoint inhibitors, which activate the immune system and destroy cancer cells. therapy was included.

In a multicenter phase I/II study of eight patients, all patients experienced disease progression while taking both immunosuppressants and one checkpoint inhibitor. However, after adding a second checkpoint inhibitor to the regimen, two of her six patients experienced a complete response. This means the tumor has completely regressed.These results were published on January 22nd. Journal of Clinical Oncologyled to the initiation of follow-up studies testing different combinations of immune-based treatments in this patient population.

To our knowledge, this study prospectively tested whether low-dose tacrolimus (a drug used to prevent organ rejection) and prednisone could save a patient’s transplanted kidney, while also This is the first study to test whether immune checkpoint inhibitors can enable tumor regression in transplant recipients. skin cancer. These results provide important insight into the effects of this combination therapy on the immune system and may help us better understand how to monitor the health of transplanted organs when patients receive these drugs. Helpful. ”

Evan Lipson, MD, Senior Author and Principal Investigator, Associate Professor of Oncology, Johns Hopkins University School of Medicine and Kimmel Cancer Center

Organ transplant recipients have a significantly higher incidence of skin cancer than the general population because they are given long-term immunosuppressive drugs to prevent rejection of the transplanted organ. This may “soothe” the immune system so it won’t recognize or attack cancer if it develops, Lipson said.

“This is a major unmet medical need, especially in this patient population, because these skin cancers are painful, disfiguring, aggressive, and deadly,” he says. “Ideally, we want to help the patient’s immune system wake up enough to attack these cancers, but not so activated that it starts rejecting the transplanted organ.”

The Experimental Therapeutics Clinical Trials Network (ETCTN) trial includes patients with advanced melanoma, cutaneous squamous cell carcinoma, or Eight patients with cell carcinoma participated. All participants had previously undergone a kidney transplant and had adequate renal function at the time of study enrollment. The average time from kidney transplant to trial initiation was 13 years. All patients agreed to undergo dialysis if the treatment regimen resulted in renal failure. ETCTN is a National Cancer Institute-funded network established to evaluate innovative cancer treatments through collaborative early-phase clinical trials nationwide.

Participants received standard immunosuppressive therapy with low-dose tacrolimus and prednisone. After the researchers confirmed that kidney function was stable on this regimen, they added the immune checkpoint inhibitor nivolumab. Nivolumab inhibits the PD-1 protein and is approved by the FDA to treat patients with melanoma and other types of cancer. All eight patients experienced progressive disease. The researchers then added a second checkpoint inhibitor, the CTLA-4 inhibitor ipilimumab, to the existing three-drug regimen in six patients.

The researchers performed tumor biopsies to assess the immune response before and after nivolumab administration. Initial tumor biopsies showed an almost complete lack of infiltrating immune cells in all but one, indicating that the patient’s immune system was essentially inactive against the cancer. Ta. Of the five biopsies taken while the patient was receiving nivolumab, two showed moderate immune infiltration, indicating that the immune system had begun to attack the skin cancer. Researchers then added ipilimumab to nivolumab, and both of these patients had complete responses.

The researchers also measured donor-derived cell-free DNA levels every two weeks to study its feasibility as a potential predictor of graft rejection. Donor-derived cell-free DNA is a quantitative blood-based graft rejection marker used to monitor graft health in the non-oncology setting post-transplant, but not in the oncology setting of kidney transplant recipients. Its usefulness in is little known.

The study did not meet its primary composite endpoint of stable disease without partial or complete tumor response or graft loss after 16 weeks. Three patients experienced treatment-related graft loss at various times during the study.

Nevertheless, Lipson believes the trial is an important step forward. “The immunosuppression we chose prevented nivolumab (anti-PD-1) from reaching its full potential, but also did not fully protect the kidneys,” he said. . “We also found that only when we added a second checkpoint inhibitor did the immune system actually start attacking the cancer.”

Another important finding was that in two of three patients whose transplanted kidneys were damaged by the investigational drug, levels of donor-derived cell-free DNA were 10% higher than the increase in serum creatinine, an indicator of kidney health. There was an increase in the number of days before and 15 days ago. “In the future, this knowledge may help us intervene earlier and better preserve transplanted organs, which are a precious resource,” Lipson said.

The research team has already begun work on a follow-up trial in which prednisone and the immunosuppressant sirolimus are given together, as well as two immune checkpoint inhibitors, nivolumab and ipilimumab. “In the completed study, two checkpoint inhibitors were introduced sequentially because we did not want to overstimulate the patient’s immune system and risk harming the transplanted organ,” Lipson said. “But some skin tumors grow so quickly that I can’t wait to give my second immunotherapy drug a few months after starting my first one.”

The study grew out of Lipson’s pioneering work a decade ago, when he was the lead author on a pair of case reports also published in the journal. Journal of Clinical Oncology, Number of organ transplant recipients treated with immune checkpoint inhibitors for metastatic melanoma.

Other study co-authors include Kara M. Schenk, Julie Stein, Megan D. Schollenberger, William H. Sharfman, Kristin P. Bibee, Jeffrey F. Scott, Manisha J. Loss, Hao Wang, Janis M. Taube, Suzanne L. Topalian, Selina M. Bagnasco, and Daniel C. Brennan of Johns Hopkins. Other researchers contributing to the study were from Bozeman Health Deaconess Cancer Center in Bozeman, Montana. Northwestern University Robert H. Lurie Comprehensive Cancer Center in Chicago. UPMC (University of Pittsburgh) Hillman Cancer Center; Moffitt Cancer Center and Research Institute, Tampa, Florida. Dana-Farber Cancer Institute, Brigham and Women’s Hospital. Northwestern University Feinberg School of Medicine, Chicago. Northern Virginia Clinical Skin Center (Fairfax, VA) National Cancer Institute, Division of Investigational Drugs, Cancer Treatment Evaluation Program.

This research was supported by the National Cancer Institute (grant UM1 CA186691), the Bloomberg Kimmel Institute for Cancer Immunotherapy, the Marilyn and Michael Grosserman Foundation for Basal Cell Carcinoma and Melanoma Research, and the Mary Jo and Brian Glosserman Foundation. C. Rogers Foundation, Melanoma of Delaware, the Barney Family Foundation, the Ravana Hahn Charitable Trust, Bristol-Myers Squibb, and the Raymond and Melody Ranelli Foundation.