Multiple High-Grade and Rare Immune-Related Adverse Events in a Colon Cancer Patient with Genomic and Cytokine Profiling

Abstract

We report a case of multiple high-grade and rare immune-related adverse events (irAEs) in a patient with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A middle-aged MSI-H mCRC patient with metastases to the lungs and lymph nodes received several lines of chemotherapy and immunotherapy and developed five different high-grade irAEs during immunotherapy, including lymphadenitis, pneumonitis, hypophysitis, thyroiditis and transverse myelitis. Genomic profiling revealed high tumor mutational burden of 43 Muts/Mb. Cytokine profiling showed a threefold increase in MMP-9 shortly prior to the onset of lymphadenitis and a fourfold increase of Ang-1 1 week after the resolution of lymphadenitis. Further studies are warranted to investigate the association of MSI-H mCRC with irAEs and the role of cytokines in predicting irAEs.

Plain language summary

Immune-related adverse events (irAEs) are a potential side effect of taking immunotherapy treatment for cancer. We report a case of a patient with a highly mutated form of metastatic colon cancer who developed five unique and severe irAEs while receiving immunotherapy. The patient developed inflammation of the lymph nodes, lungs, pituitary gland, thyroid and spinal cord. Genetic testing showed that the tumor was highly mutated (43 Muts/Mb). Analysis of cell signaling proteins called cytokines revealed that MMP-9 sharply increased before the onset of lymphadenitis and Ang-1 sharply increased after its resolution. Further research is needed to understand the relationship between highly mutated colon cancer and irAEs as well as the role of cytokines in predicting the onset and resolution of irAEs.

Keywords::

• anti-PD-1
• GITR
• hypophysitis
• immune checkpoint inhibitor
• immune-related adverse events
• lymphadenitis
• pneumonitis
• thyroiditis
• transverse myelitis

Financial & competing interests disclosure

KT reports employment at Blackstone Life Sciences. HV reports employment at Marinus Pharmaceuticals. SG reports employment as a gastroenterology editor at UpToDate, Wolters Kluwer Inc. SH reports the following: grants from BMS and Novartis; personal fees from BMS, Merck, Serono, Novartis, Takeda, Surface Pharmaceuticals, Genentech/Roche, Compass Therapeutics, Apricity, Bayer, Aduro, Partners Therapeutics, Sanofi, Pfizer, Pionyr Immunotherapeutics, 7 Hills Pharma, Verastem Oncology, Rheos Medicines, and Kairos Therapeutics; equity in Torque Therapeutics; and patents #20100111973 and #7250291 issued as well as #20170248603, #20160340407, #20160046716, #20140004112, #20170022275, #20170008962, and “Methods of Using Pembrolizumab and Trebananib” pending. OER has research support from Merck. Speaker for activities supported by educational grants from BMS and Merck. Consultant for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi. In addition, OER has patent “Methods of using pembrolizumab and trebananib” pending. In addition, OER reports employment at Astrazeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The patient evaluated in this study was identified from the Dana-Farber Cancer Institute IRB approved protocol 16-306. The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

KT reports employment at Blackstone Life Sciences. HV reports employment at Marinus Pharmaceuticals. SG reports employment as a gastroenterology editor at UpToDate, Wolters Kluwer Inc. SH reports the following: grants from BMS and Novartis; personal fees from BMS, Merck, Serono, Novartis, Takeda, Surface Pharmaceuticals, Genentech/Roche, Compass Therapeutics, Apricity, Bayer, Aduro, Partners Therapeutics, Sanofi, Pfizer, Pionyr Immunotherapeutics, 7 Hills Pharma, Verastem Oncology, Rheos Medicines, and Kairos Therapeutics; equity in Torque Therapeutics; and patents #20100111973 and #7250291 issued as well as #20170248603, #20160340407, #20160046716, #20140004112, #20170022275, #20170008962, and “Methods of Using Pembrolizumab and Trebananib” pending. OER has research support from Merck. Speaker for activities supported by educational grants from BMS and Merck. Consultant for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi. In addition, OER has patent “Methods of using pembrolizumab and trebananib” pending. In addition, OER reports employment at Astrazeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.