Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature

Abstract

Background Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT. Methods Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs. Results Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14–79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92–32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3–22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs. Conclusions SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients. Electronic supplementary material The online version of this article (10.1186/s40425-019-0585-1) contains supplementary material, which is available to authorized users.

Epidemiologic perspectives on immunosuppressed populations and the immunosurveillance and immunocontainment of cancer

“…11 Atezolizumab was recently approved for treatment of triple-negative breast cancer (ie, tumors lacking expression of estrogen receptor, progesterone receptor, and human epidermal growth factor 2). [89][90][91] One issue is that key characteristics of these tumors that predict response to checkpoint blockade (eg, PD-L1 expression, TMB) have not been systematically assessed in these immunosuppressed populations. 88 Finally, there is substantial interest in using checkpoint inhibitors to treat SOTRs and HIV-infected people with cancer.…”

“…88 Finally, there is substantial interest in using checkpoint inhibitors to treat SOTRs and HIV-infected people with cancer. [89][90][91] One issue is that key characteristics of these tumors that predict response to checkpoint blockade (eg, PD-L1 expression, TMB) have not been systematically assessed in these immunosuppressed populations. Indeed, it is possible that the loss of T cell immunity due to other mechanisms (ie, immunosuppressant medications, AIDS) reduces immune-selective pressure, thus obviating the need for tumors to express checkpoint proteins, in which case checkpoint inhibitor treatment might be ineffective.…”

“…18 Case reports of checkpoint blockade for treatment of advanced skin cancers in SOTRs have described modest efficacy but there appears to be substantial risk of graft rejection as a complication of treatment. 89,90 At least 1 phase 1 trial is planned to assess this approach further (https ://clini caltr ials.gov NCT03816332).…”

Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient?

“…In 1 review, 3 of 4 liver transplant recipients aged 14 to 53 years who received nivolumab for recurrent HCC died within 5 weeks of treatment because of what was described as combined cellular and antibody‐mediated rejection . Other reviews have described similar concerning outcomes with the use of ICIs after solid organ transplant . Thus, although the rate of allorejection is not well defined in large‐scale clinical trials, this and other cases highlight the need for extreme caution surrounding ICI use in the peritransplant or posttransplant setting.…”

“…Since 2017, there have been several reports of the use of ICIs, such as nivolumab, in solid organ transplant recipients as an adjuvant therapy for recurrent HCC or melanoma. Many of these reports describe a severe and often fatal alloimmune injury, even when the drug was introduced years after transplant . We present in this case report the first published use of nivolumab in the pretransplant setting for HCC.…”