On the contrary, many checkpoint inhibitors are currently approved specifically for patients who have failed standard therapies such as bone marrow transplants.
- Experimental cancer therapies such as immunotherapies are first trialed (clinical trials) in very sick patients. Often such patients may have failed therapies that are the prevailing standard for their cancers.
- Bone marrow stem cell transplants (both from self or autologous or from genetically dissimilar or allogeneic) are part of standard line treatments in many blood cancers.
This is why the FDA approved checkpoint inhibitors such as nivolumab and pembrolizumab for classical Hodgkin lymphoma on the basis of results in patients who had either relapsed or progressed after autologous or allogeneic hematopoietic stem cell transplants (below, emphasis mine).
- Younes, Anas, et al. “Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial.” The Lancet Oncology 17.9 (2016): 1283-1294. Nivolumab for classical Hodgkin lymphoma after autologous stem-cell transplantation and brentuximab vedotin failure: a prospective phase 2 multi-cohort study
- Herbaux, Charles, et al. “Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma.” Blood 129.18 (2017): 2471-2478. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma).
- Chen, Robert, et al. “Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma.” Journal of Clinical Oncology 35.19 (2017): 2125. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma
However, clinicians are also now beginning to appreciate that such treatment entails higher risk of graft-versus-host disease in both bone marrow and solid organ transplant recipients (below, emphasis mine). Such risk isn’t surprising since PD1 and CTLA-4 pathways have important, non-redundant roles in restraining T cell activation, especially in the context of autoimmunity. No surprise that these same pathways are also at play in establishing immunological tolerance to organ transplants as well.
- Singh, A. K., et al. “Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin’s lymphoma.” Bone marrow transplantation 51.9 (2016): 1268. Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin’s lymphoma
- Haverkos, Bradley M., et al. “PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD.” Blood 130.2 (2017): 221-228. PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD
- McDuffee, E., et al. “Tumor regression concomitant with steroid-refractory GvHD highlights the pitfalls of PD-1 blockade following allogeneic hematopoietic stem cell transplantation.” Bone marrow transplantation 52.5 (2017): 759. Tumor regression concomitant with steroid-refractory GvHD highlights the pitfalls of PD-1 blockade following allogeneic hematopoietic stem cell transplantation
- Boekstegers, A. M., et al. “MRD response in a refractory paediatric T-ALL patient through anti-programmed cell death 1 (PD-1) Ab treatment associated with induction of fatal GvHD.” Bone marrow transplantation 52.8 (2017): 1221. MRD response in a refractory paediatric T-ALL patient through anti-programmed cell death 1 (PD-1) Ab treatment associated with induction of fatal GvHD
- Oshima, Y., et al. “Association between GvHD and nivolumab in the FDA adverse event reporting system.” Bone marrow transplantation 52.10 (2017): 1463. Association between GvHD and nivolumab in the FDA adverse event reporting system
- Ijaz, Awais, et al. “Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation.” Biology of Blood and Marrow Transplantation 25.1 (2019): 94-99. ScienceDirect
- Steinerová, K., et al. “Development of Resistant GvHD in a Patient Treated with Nivolumab for Hodgkins Lymphoma Relapse after Allogeneic Unrelated Transplantation.” Klinicka onkologie: casopis Ceske a Slovenske onkologicke spolecnosti 32.1 (2019): 66-69.
Finally, case reports of both successful and unsuccessful Rx with checkpoint inhibitors in solid organ transplant recipients (kidney, liver, below, emphasis mine) are beginning to reveal key roles for drug (anti-PD1 may be more risky compared to anti-CTLA-4), type of immunosuppression used and time of Rx in shaping the outcome.
- Kittai, Adam S., et al. “Immune checkpoint inhibitors in organ transplant patients.” Journal of Immunotherapy 40.7 (2017): 277-281.
- Goldman, Jonathan W., et al. “PD 1 checkpoint inhibition in solid organ transplants: 2 sides of a coin–case report.” BMC nephrology 19.1 (2018): 210. PD 1 checkpoint inhibition in solid organ transplants: 2 sides of a coin – case report
- Herz, Saskia, et al. “Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient.” European journal of cancer 67 (2016): 66-72.
- Deltombe, Clément, et al. “Severe allograft rejection and autoimmune hemolytic anemia after anti-PD1 therapy in a kidney transplanted patient.” (2017): e291.
- Winkler, Julia K., et al. “Safe administration of an anti-PD-1 antibody to kidney-transplant patients: 2 Clinical cases and review of the literature.” Journal of Immunotherapy 40.9 (2017): 341-344.
- Lesouhaitier, Mathieu, et al. “Checkpoint blockade after kidney transplantation.” European Journal of Cancer 96 (2018): 111-114.
- Friend, Brian D., et al. “Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma.” Pediatric blood & cancer 64.12 (2017): e26682.
- Schvartsman, Gustavo, et al. “Immune checkpoint inhibitor therapy in a liver transplant recipient with melanoma.” Annals of internal medicine 167.5 (2017): 361-362.
- Gassmann, Dimitri, et al. “Liver Allograft Failure After Nivolumab Treatment—A Case Report With Systematic Literature Research.” Transplantation direct 4.8 (2018). Liver Allograft Failure After Nivolumab Treatment—A Case Report With Systematic Literature Research
- Munker, Stefan, and Enrico N. De Toni. “Use of checkpoint inhibitors in liver transplant recipients.” United European gastroenterology journal 6.7 (2018): 970-973. Use of checkpoint inhibitors in liver transplant
recipients - Rammohan, Ashwin, et al. “Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: The silver bullet?.” Hepatology 67.3 (2018): 1166-1168. Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: The silver bullet?