As the number of solid organ transplants in the United States rises, cancer in this patient population is a growing concern. In fact, solid organ transplant recipients have an up to 50 times greater risk than the general population of developing skin cancers, and for kidney transplant recipients, cancer is the third most common cause of death.1
Janice M. Mehnert, MD
“As we continue to perform more transplants, we’re going to see this problem grow,” said Janice M. Mehnert, MD, of Rutgers Cancer Institute of New Jersey in New Brunswick. “When patients who have undergone the intense experience of having a solid organ transplant are told that they have cancer that may be related to their immunosuppressants, it’s a very emotionally charged situation. It’s important to put our heads together to figure out how to deal with this issue.”
Dr. Mehnert delivered the talk on immunotherapy in solid organ transplants at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium, filling in for Evan J. Lipson, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.
Challenges to This Population
As Dr. Mehnert reported, the number of solid organ transplants performed in the United States has tripled in the past 30 years, and these patients are often challenged with comorbidities or medical frailty. Patients with the highest risk for cancer in this population tend to be older, further removed from transplantation, and on active immunosuppression, including azathioprine, cyclosporine, and mTOR inhibitors. Until now, however, this patient population has been excluded from clinical trials testing immune checkpoint inhibitors in cancer.
According to Dr. Mehnert, given the difficulties faced by solid organ transplant recipients and the high risks associated with treatment, discussing goals of care assumes even greater importance. “A lot of these patients have been through quite a bit already,” she said. “A kidney transplant patient often knows exactly what dialysis means and will say, ‘I don’t want to undergo that risk’ or ‘I can live on dialysis’ if the kidney is rejected. As you’re embarking on any kind of treatment course, whether it’s off protocol or on protocol, discussion with patients is critical.”
Formulating a Strategy
As Dr. Mehnert explained, the programmed cell death protein 1 (PD-1) pathway plays an important role in both cancer development/suppression and allograft tolerance/rejection. Tumors arising in chronically immunosuppressed patients may contain immune-reactive tumor microenvironments, said Dr. Mehnert, and as a result, they should be considered for anti–PD-1 therapy.
“If we administer immune checkpoint blockade, this can be highly effective against cancers arising in the context of chronic immunosuppression, but then we also run the risk of triggering a T-cell–mediated allograft rejection or loss,” she explained. “This is obviously a tricky and emotionally charged conversation.”
What little is known about the safety and eficacy of immune checkpoint inhibitors in solid organ transplant recipients comes from approximately 100 cases in the medical literature. The patients described in those reports comprise a diverse group with various transplanted organs and tumor types who received a variety of immunosuppression and immune checkpoint inhibitor regimens. Therefore, Dr. Lipson explained in an interview after the ASCO-SITC meeting, drawing conclusions about optimization of tumor and allograft outcomes is challenging. In order to prospectively address this data gap, Dr. Lipson and his colleagues are testing a combinatorial treatment regimen designed to activate antitumor immunity and minimize immune-mediated allograft rejection.
“The goal is to devise a safe and effective immunotherapy regimen against cancers arising in kidney transplant recipients while maintaining allograft preservation,” said Dr. Mehnert, who underscored the immune system’s “delicate balance” between immune activation and immune suppression. “The key is to alternate immunosuppression in a rational way with the immunotherapy both to energize the immune system and dampen down the graft rejection.”
Nivolumab, Tacrolimus, and Prednisone for Cancers After Kidney Transplant
Dr. Lipson’s trial is an investigator-initiated phase II study being conducted through the Experimental Therapeutics Clinical Trials Network (ETCTN), a network of collaborative centers funded by the National Cancer Institute that spans North America. The lead clinical trial site is Johns Hopkins, with Dr. Lipson serving as principal investigator. The goal is to enroll 9 to 16 kidney transplant recipients.
“Dr. Evan Lipson and colleagues are focused on cancers that are known to be fairly responsive to immunotherapy—Merkel cell carcinoma, melanoma, basal cell carcinoma, cutaneous squamous cell carcinoma, and microsatellite instability–high cancers—to optimize the chance of response,” said Dr. Mehnert.
The trial design involves treatment with nivolumab (480 mg every 4 weeks), with the addition of ipilimumab in cases of tumor progression. Tacrolimus and prednisone will be administered for graft preservation. The study’s primary endpoint is the proportion of patients experiencing a complete response, partial response, or stable disease without allograft loss at 16 weeks.
The exploratory objectives of this trial are to study the immunologic changes in the tumor microenvironment (for example, changes in T-cell subset populations or expression of immune checkpoint molecules) in paired biopsies obtained pretreatment and on-treatment. Investigators will also assess changes in donor-derived, cell-free DNA as an early marker of allograft rejection and describe characteristics of immune-mediated adverse reactions in this patient population treated with immunosuppression.
Risk-Benefit Discussion Critical
In the meantime, as this trial gets underway, solid organ transplant recipients and their physicians will continue to face difficult treatment decisions, including whether to administer immunotherapy at all.
In a similar manner, any recipient of a solid organ transplant embarking on treatment with an immune checkpoint inhibitor needs to have a “very thorough risk-benefit discussion,” after which the oncologist needs to be extra vigilant, she said.
“This is uncharted territory,” Dr. Mehnert said in conclusion. “Working together, I think we can all try to get some better answers to make this a less tricky clinical question, but we still have a lot of work to do.”
DISCLOSURE: Dr. Mehnert has received honoraria from EMD Serono and Pfizer/EMD Serono; has served in a consulting or advisory role for Amgen, Array BioPharma, Boehringer Ingelheim, Merck Sharp & Dohme, and Sanofi/Regeneron; and has received institutional research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, Immunocore, Incyte, MacroGenics, Merck, Novartis, Polynoma, and Sanofi. Dr. Lipson has served in a consulting or advisory role for Array BioPharma, Bristol-Myers Squibb, EMD Serono, MacroGenics, Merck, Novartis, Regeneron, and Sanofi; and has received research funding from Bristol-Myers Squibb, Merck, and Regeneron.
1. Mehnert JM, for Lipson EJ: Checkpoint inhibitors in patients with solid organ transplant. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Invited lecture. Presented February 7, 2020.