Excessive Immune Reactions Caused by Ipilimumab

Ipilimumab, also known as Y-drug or anti-CTLA4 monoclonal antibody, is a recombinant humanized monoclonal antibody developed by Bristol-Myers Squibb that binds to cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Since March 25, 2011, when the US FDA approved Yervoy (3 mg/kg) monotherapy for unresectable or metastatic melanoma, more than 50 countries worldwide, including China, have successively approved its use. Currently, besides treating mid-to-late stage melanoma, this drug is also used for colorectal cancer, non-small cell lung cancer, advanced renal cell carcinoma, and malignant pleural mesothelioma.

Yervoy achieves its anti-cancer purpose by activating the human immune system. As a CTLA-4 inhibitor, Yervoy acts on the lymph nodes in the early activation stage of T-cell development; by inhibiting the CTLA-4 signaling pathway, it releases cancer cells' suppression of T-cell proliferation, thereby helping T cells proliferate and activate in large numbers. Some of the T cells activated by Yervoy can also differentiate into memory T cells, thus remembering the battle and maintaining long-term combat strength; this is the mechanism of Yervoy's anti-cancer action.

But its side effects should not be underestimated. The activated T cells easily undergo excessive immune reactions, causing patients to frequently have symptoms similar to those after viral or bacterial infection, such as fever, muscle aches, chills, diarrhea, abdominal pain, nausea, and edema. A melanoma patient I am currently treating developed the above reactions after using Y-drug, and these reactions are not one-off but occur frequently. When the patient catches cold, is injured, eats unclean food, or even wears slightly tight clothing, the above symptoms appear, and the patient herself feels she is in an allergic state.

In fact, Y-drug can cause an immune storm, also called a cytokine storm—a fatal, abnormal immune state. Under normal immune conditions, the immune system is controlled and does not harm the body itself, but in an immune storm, various immune cells, such as T cells, macrophages, and NK cells, rapidly proliferate and become highly activated, producing large amounts of inflammatory factors and chemical mediators; while killing pathogens, they also cause immune damage to the host itself. Y-drug activates T cells and promotes their rapid proliferation, leaving them long in a combat state, so Y-drug causing an immune storm is not hard to understand. I have seen two lung cancer patients who died of immune storms after using PD-1. But both were elderly patients, one in her eighties and one in his seventies, showing that such drugs should be used cautiously in elderly patients.

Few doctors in China currently pay attention to these side effects of Y-drug and similar drugs, leaving patients who develop these side effects after using Y-drug without countermeasures. I have treated one patient using Opdivo (also known as O-drug, nivolumab) and am treating one using Y-drug; both developed this condition. The medical case of the patient I treated in 2017 who developed an excessive immune reaction after using O-drug was previously published in "A TCM Treatment Case of Patient Wang with Colon Cancer with Liver Metastasis and Advanced Double Primary Endometrial Cancer"; the treatment regimen at that time can be read by clicking the link above.

The melanoma patient I am currently treating used 3 doses of Y-drug, but the tumor not only did not regress but progressed faster, while at the same time a strong immune reaction appeared. Her problem is still being resolved; I have tried various regimens before, all with poor results. Now I am treating her according to a gastrointestinal cold regimen; after the Chinese patent medicine Huoxiang Zhengqi Oral Liquid, the patient's fever can be relieved, and after Simiao Wan, her pain also improved slightly. I previously used Guizhi Jia Gegen Tang to improve her shoulder and back soreness. But fully relieving her excessive immune reaction may still take some time.

Preparations like nivolumab and ipilimumab do have a certain efficacy, but they are not effective for every patient, and their side effects are very large. Therefore patients must observe carefully when using them; if they are ineffective and the side effects are too great, treatment should be stopped promptly, and clinicians should also find auxiliary treatment regimens for patients.

When treating these kinds of side effects, TCM may have an advantage over Western medicine, because from the reactions of these two patients we can see that different patients' body reactions after using immune preparations are not entirely the same, making it hard to find a unified standardized treatment regimen for them. TCM can instead differentiate and treat based on the patient's clinical symptoms to find the corresponding treatment regimen.

For example, the patient using O-drug above only had edema and severe pain; at that time I treated her with combined formulas of Wuling San, Huangqi Fangji Tang, and Simiao Wan, relieving her suffering. The patient I am currently treating, however, has reactions of abdominal pain, diarrhea, chills, excessive sweating, fever, and muscle aches—symptoms similar to a gastrointestinal cold, and it being summer, the exterior-releasing and damp-transforming, qi-regulating and middle-harmonizing Huoxiang Zhengqi Oral Liquid is more symptomatic. After these two patients developed the above excessive immune reactions following treatment with nivolumab and ipilimumab, Western medicine had no good strategies and had to turn to TCM.