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Inclusion of Immunosuppressed Patients in Oncology Clinical Research:
Promises and Challenges of Immune-Based Therapeutic Strategies

May 2020

Vulnerable Populations in Oncology

The past decade has been an exciting time in the field of cancer clinical research. The development of immune checkpoint inhibitors (ICIs) provides a promising new treatment modality for a wide variety of cancers. Since the first FDA approval of an ICI for treatment of melanoma in 2011, use of this drug class expanded to numerous other cancer types, thereby dramatically increasing the number of patients who could potentially benefit from ICI therapy.1,2 However, each cancer patient is unique, and significant safety concerns have precluded clinical testing of many cancer treatments, including ICIs, in patients with other preexisting conditions. Patients with underlying immunological complications, such as those with autoimmune diseases or those who received a solid organ transplant (SOT), constitute one such group that has been historically excluded from cancer clinical research.1,2 Autoimmune diseases affect an estimated 14.7 to 23.5 million people in the United States (about 5-8% of the population3), and the annual rate of SOTs has increased steadily since 2012, with nearly 40,000 SOTs performed in 2019.4 Concerns of significant drug-drug interactions, exacerbation of preexisting conditions, and unforeseen side effects have prevented the systematic evaluation of effective cancer therapeutics in these patient populations.

One overarching function of the immune system is to recognize and destroy “foreign” substances in the body (for example, harmful bacteria and viruses), while ignoring the tissues of the body as “self.” Autoimmune diseases, such as lupus, rheumatoid arthritis, celiac disease, and psoriasis, are characterized by a dysfunctional immune system that mistakes some part of the body as foreign and attacks it, causing tissue or organ damage and jeopardizing the life of the patient. In SOT recipients, the foreign substance (the transplanted organ or tissue) is desired and must be protected from rejection by the immune system. Immunosuppression, the pharmaceutical strategy of reducing immune system activity, is critical for the health and survival of these patient groups.

Because of the nature of their diseases and immunosuppressive regimens, these patients have an increased risk of developing cancer. Inflammation due to autoimmune diseases heightens the risk of malignancy, and immunosuppressive drugs reduce immune system surveillance and destruction of tumors.5,6 It is therefore imperative to include these patients in the clinical testing of potentially safe and effective new cancer therapeutic strategies, such as ICIs.

However, the concerns related to testing ICIs in immunosuppressed patients are not unwarranted. These drugs work by blocking inhibitory signals that would prevent the immune system from attacking tumors.7 ICIs are the exact opposite of immunosuppressive drugs; their function leads to activation of the immune system in order to control, shrink, or destroy tumors. This activity has side effects. ICIs are known to cause a wide range of transient and chronic immune-related Adverse Events (irAEs). The American Society of Clinical Oncology and the National Comprehensive Cancer Network jointly published a comprehensive set of clinical guidelines for the monitoring and management of irAEs in cancer patients receiving ICI therapy.7

This “unleashing” of the immune system is, in theory, precisely what should be avoided in patients with autoimmune diseases and recipients of SOTs. Yet without testing ICI regimens in immunosuppressed patients, these groups often receive inferior or ineffective cancer therapies. Treating physicians do not want to risk exacerbation of immune dysfunction or transplant rejections that could further endanger the lives of their patients. Because of this dilemma, cancer remains a prevalent health concern for patients with autoimmune diseases and a leading cause of death for SOT recipients,8 reinforcing the notion that these underserved populations should not be excluded from clinical testing of new cancer treatments like ICIs.

Reports of ICI use in immunosuppressed populations to date remain anecdotal. However, several retrospective safety and efficacy analyses have been performed for ICI use in cancer patients with preexisting autoimmune diseases or who received a prior SOT.1,2,9,10 These retrospective studies’ results demonstrate that, like cancer patients, all immunosuppressed patients are unique, and ICI therapy may be safe and effective for some patients but not others.

For patients with autoimmune diseases, the results seem promising. ICI use in these patients did commonly cause exacerbation of their underlying disorders, as well as instances of new unrelated irAEs.1,9,10 However, as in patients without autoimmune diseases, side effects were generally manageable with corticosteroids, and most patients continued ICI therapy. Moreover, ICI use in these patients showed clinical benefit regardless of whether patients were taking immunosuppressive drugs at the time of ICI use. These preliminary results lay the foundation for more comprehensive evaluation of ICI therapy in cancer patients with underlying autoimmune diseases.

ICI therapy in SOT recipients appears more complicated. While irAEs were few and manageable, nearly half of the patients studied suffered transplant rejection, and most of those cases ended in transplant loss and death, despite stopping ICI therapy.2 However, this retrospective analysis consisted of 39 patients, hardly a large enough sample to extrapolate to the larger population of SOT recipients with cancer. A recent case report suggests this therapeutic strategy is not wholly without promise.11 A liver transplant recipient who developed colorectal cancer was treated with the ICI pembrolizumab after chemotherapy failed to prevent development of a new bowel obstruction and liver metastases. The bowel obstruction resolved after 6 weeks of ICI therapy, his liver function tests normalized after 9 weeks, and CT scans of his liver showed a sustained shrinkage of metastatic tumors at 36 weeks. At the time of the case report, the patient had completed 11 months of ICI treatment with no significant safety concerns. While this case gives cause for optimism, use of ICI regimens in SOT recipients should be systematically evaluated to maximize therapeutic benefit while minimizing harmful side effects.

Recently, two clinical trials sponsored by the National Cancer Institute (NCI) began testing ICI therapies in each of these patient populations. The first study, led by clinicians and researchers at the MD Anderson Cancer Center in Houston, Texas, is an evaluation of one ICI in patients with several different autoimmune diseases and a wide range of cancers.12,13 The second study, at Johns Hopkins University, tests a combination of two different ICIs in cancer patients who received prior kidney transplants.14 These Phase 1 trials focus primarily on the safety profiles of the given ICI regimens in their respective patient populations. However, researchers will still monitor the drugs’ effectiveness in treating the patients’ cancers to support decisions about further clinical development of the ICI regimens in these patient groups. While these trials have only begun recruiting patients, they promise to yield critical information about the benefits and risks of immune-based therapies for cancer patients with immune disorders.

These two groundbreaking trials are not without limitations. Both studies test only one or two defined ICI regimens in their patient groups, and the latter tests its regimen only in patients receiving kidney transplants. Just as not all cancer patients are equal, not all autoimmune diseases nor SOTs are the same. The retrospective analyses of ICI therapy in these populations identified potential differences in side effect type, prevalence, and severity, as well as treatment effectiveness that depends on the ICI regimen tested, the particular underlying autoimmune disease or transplanted organ, and other patient-distinguishing factors.1,2,9,10 These analyses indicate the need for rigorous combinatorial testing of various ICI regimens in patients with particular cancers and with specific autoimmune diseases or who have received specific transplanted organs. Ideally, the two aforementioned NCI-sponsored ICI trials will pave the way for this comprehensive evaluation to ensure patients receive the safest and most effective treatment option currently available to them.

Given its long-standing relationship with the National Cancer Institute, Technical Resources International has extensive experience managing several aspects of oncology clinical research. In particular, TRI utilizes its network of contacts in the oncology field to develop and implement specialized patient recruitment and retention strategies for clinical trials sponsored by the NCI. This service will help to ensure effective communication on the availability of ICI trials open to immunosuppressed patients with cancer to oncologists and their eligible patients. TRI also provides clinical protocol development services and comprehensive patient safety monitoring relevant to the inclusion of underserved patient populations in cancer clinical trials. The highly experienced clinical research staff at TRI are well poised to contribute to the goal of ensuring that patients with autoimmune diseases and SOT recipients have access to potentially lifesaving new cancer treatments.


  1. Abdel-Wahab N, Shah M, Lopez-Olivo MA, et al. Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease. Ann Intern Med 2018; 168:121-130. Available at:

  2. Abdel-Wahab N, Safa H, Abudayyeh A, et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J Immunother Cancer 2019; 7:106. Available at:

  3. Desai MK and Brinton RD. Autoimmune Disease in Women: Endocrine Transition and Risk Across the Lifespan. Front Endocrinol (Lausanne) 2019; 10:265. Available at:

  4. Organ Procurement and Transplantation Network National Data Report: Transplants by Donor Type. Available at: (Accessed February 19, 2020.)

  5. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36:1714-1768. Available at:

  6. Giat E, Ehrenfeld M, Shoenfeld Y. Cancer and autoimmune diseases. Autoimmun Rev 2017; 16:1049-1057. Available at:

  7. Koff JL and Waller EK. Improving Cancer-Specific Outcomes in Solid Organ Transplant Recipients: Where to Begin? Cancer 2019; 125:838-842. Available at:

  8. Acuna SA, Fernandes KA, Daly C, et al. Cancer Mortality Among Recipients of Solid-Organ Transplants in Ontario, Canada. JAMA Oncol 2016; 2:463-469. Available at:

  9. Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 2017; 28:368-376. Available at:

  10. Johnson DB, Sullivan RJ, Ott PA, et al. Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA Oncol 2016; 2:234-240. Available at:

  11. Chen JA, Esteghamat N, Kim EJ, et al. PD-1 Blockade in a Liver Transplant Recipient With Microsatellite Unstable Metastatic Colorectal Cancer and Hepatic Impairment. J Natl Compr Canc Netw 2019; 17:1026-1030. Available at:

  12. Nivolumab in Treating Patients With Autoimmune Disorders or Advanced, Metastatic, or Unresectable Cancer. 2019. Retrieved from (Identification No. NCT03816345)

  13. National Cancer Institute. 2019. Study Tests Immunotherapy in People with Cancer and Autoimmune Diseases. Available at:

  14. Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers. 2019. Retrieved from
  15. (Identification No. NCT03816332)

About the Author

Christopher Slagle is a medical writer and clinical research specialist at TRI. He earned a PhD in Molecular Biology from Princeton University and has over fifteen years of combined experience in biomedical research and scientific writing.






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