When the first immunotherapy drug ipilimumab (Yervoy) was FDA approved in 2011, immunotherapy was hailed as a “breakthrough” in cancer treatment. This much-anticipated new therapy harnessed the power of the body’s immune system to fight cancer. Fast forward to today and, unfortunately, only a minority of cancer patients truly benefit from immunotherapy in terms of tumor shrinkage, and even fewer experience long-term remission or cures as a result.
Why didn’t immunotherapy live up to its hype? It turns out that, just as cancer cells can be inherently chemoresistant or radioresistant (resistant to chemotherapy or radiation therapy) or can acquire chemoresistance or radioresistance, cancer cells can be inherently immunoresistant (resistant to immunotherapy) or can acquire immunoresistance. Also, just as there can be serious side effects with chemotherapy or radiation therapy, the same is true for immunotherapy.
One of the potential side effects of immunotherapy is the development of autoimmune reactions. Autoimmune side effects occur when the immune system, which is being stimulated to fight cancer cells, mistakenly attacks healthy cells and tissues in the body. This can lead to a range of autoimmune-related side effects which may necessitate discontinuation of treatment. Autoimmune side effects of immunotherapy can include:
- Dermatologic reactions: Skin-related side effects such as rash, itching, or dry skin can occur. In more severe cases, blistering or peeling skin may develop.
- Colitis: Immunotherapy can cause inflammation in the gastrointestinal tract, leading to symptoms such as diarrhea, nausea, vomiting, abdominal pain, and, in severe cases, colitis.
- Hepatitis: Liver inflammation or hepatitis may occur, leading to elevated liver enzymes, fatigue, and jaundice.
- Endocrinopathies: The endocrine system can be affected by immunotherapy, resulting in conditions such as hypothyroidism, hyperthyroidism, adrenal insufficiency, or type 1 diabetes.
- Pneumonitis: Inflammation in the lungs, also known as pneumonitis, can cause symptoms such as shortness of breath, cough, and chest pain.
- Neurological problems: These can range from peripheral neuropathy (numbness and tingling in the extremities) to more severe conditions like meningitis, encephalitis, or seizures.
- Myocarditis: Inflammation of the heart muscle, causing symptoms like chest pain, shortness of breath, or fatigue.
- Nephritis: Inflammation of the kidneys, potentially leading to reduced kidney function or kidney failure. Symptoms might include changes in the amount of urine produced, blood in the urine, or swelling in the legs.
- Arthritis and joint pain: Pain, swelling, or stiffness in the joints.
- Hematologic: Immunotherapy can lead to blood-related side effects such as anemia, thrombocytopenia, or neutropenia.
- Sicca syndrome: Dry eyes or mouth due to inflammation of tear and salivary glands.
To combat immunoresistance, promote immunosensitization of cancer cells (sensitizing them to immunotherapy), and inhibit immunotherapy-induced autoimmunity, the following should be considered:
Suppression of interleukin-6 (IL-6):
IL-6 is a cytokine, which is a type of signaling molecule produced by immune cells and other cell types in the body. IL-6 has various functions, including the regulation of immune responses, inflammation, and hematopoiesis (the formation of blood cells). In the context of tumors, IL-6 can play a significant role in promoting tumor growth, immune evasion, and cancer progression. Tumor cells and the surrounding cells in the tumor microenvironment can produce IL-6. IL-6 receptor blockade was found to increase the efficacy of immunotherapy while mitigating immunotherapy-induced autoimmunity.
There are several prescription medications that block IL-6, which are commercially available for clinical use:
- Sarilumab (Kevzara): This is another IL-6 receptor antagonist that has been approved by the FDA.
- Satralizumab: This is also a monoclonal antibody directed against the IL-6 receptor.
- Siltuximab (Sylvant): This is a monoclonal antibody specific for IL-61. It is approved for the treatment of human immunodeficiency virus-negative and HHV-8-negative patients with multicentric Castleman’s disease.
- Tocilizumab (Actemra): This is a monoclonal antibody directed against the IL-6 receptor. It is also approved by the FDA for the treatment of rheumatoid arthritis.
Please note that while the above medications can be effective, they can also have serious side effects. Always consult with a qualified healthcare provider before starting any new treatment regimen.
Natural products that can inhibit IL-6 include:
- Apigenin
- Sulforaphane
Metabolic reprogramming using calorie-restriction mimetics:
Calorie restriction refers to a dietary regimen that involves reducing calorie intake without causing malnutrition. Calorie restriction has been found to improve the function of immune cells, such as T cells and natural killer cells, and enhance their ability to target and kill cancer cells. Calorie restriction mimetics (CRMs) are compounds that can mimic the physiological calorie restriction without the need for reducing calorie intake. Emerging data has shown that the use of CRMs may serve as an important adjuvant to immunotherapy.
Prescription medications that can act as CRMs include:
- Metformin
- Rapamycin
Natural compounds that can act as CRMs include:
- Glucosamine
- Hydroxycitric acid
Blocking of histamine receptor H1 (HRH1):
Tumors can “polarize” cancer-killing M1 macrophages by changing them to cancer tumor-promoting and T-cell-inhibiting M2 macrophages (also known as tumor-associated macrophages or TAMs). High levels of histamine in the tumor environment bind to HRH1 receptors on the surface of tumor-associated macrophages and contribute to the suppression of T-cell function, resulting in tumor resistance to immunotherapy. Antihistamines were found to block the histamine receptors on macrophages, thereby blocking their polarization from M1 to M2 macrophages, thus resulting in restored T-cell antitumor activity.
Here are over-the-counter antihistamines that are considered non-drowsy:
- Fexofenadine (Allegra)
- Cetirizine (Zyrtec)
- Loratadine (Claritin)
Overcoming the challenge of ‘exhausted’ T cells:
T-cells, also known as T lymphocytes, are a type of white blood cell that plays a central role in the immune system. They help protect the body against infections and diseases by recognizing and eliminating foreign invaders such as viruses, bacteria, parasites, and cancer cells. CD8+ T cells are the main “assassins” of cancer cells. They directly target and kill infected or cancerous cells by recognizing specific antigens (foreign substances) presented on the surface of these cells. Cytotoxic T cells release molecules like perforin and granzymes that induce apoptosis (programmed cell death) in the target cells.
Cancer immunotherapy depends on mobilizing T cells to target and eliminate tumor cells. T cells are not as effective against cancer as expected, however. A critical obstacle for immunotherapy is the decline in T cells’ capacity to destroy, commonly known as exhaustion. Prolonged activation of the immune system as seen in chronic viral infections or the gradual progression of cancer, or overstimulation of the immune system from immunotherapy, can cause T cells to tire and lose their effectiveness. T-cell exhaustion is a major pathway of resistance to immunotherapy.
Prescription medications that have been found to reinvigorate T-cell function and possibly improve the efficacy of immunotherapy by sustaining the cytotoxic activity of T-cells include:
- Metformin
- Tadalafil
Natural products that have been found to target T-cell exhaustion include:
- Sulforaphane
- Triterpenoid saponins
In the modern era of cancer treatment, immunotherapy emerged as a groundbreaking approach, promising to harness the innate power of the body’s immune system against malignancies. However, the intervening years since the FDA approval of ipilimumab (Yervoy) in 2011 have painted a more nuanced picture. Only a fraction of cancer patients realize substantial tumor reductions, with a smaller subset achieving long-term remission. The culprit, in many cases, is the presence of immunoresistance, either inherent or acquired, in cancer cells. Similar to the resistance observed with chemotherapy or radiation therapy, the immune evasion by cancer cells presents a significant challenge. Moreover, the induction of autoimmunity in some patients due to heightened immune responses poses additional challenges, causing them to experience a myriad of side effects.
Still, the fight is far from over. Emerging strategies, from suppressing IL-6, and utilizing calorie-restriction mimetics, to blocking histamine receptors and rejuvenating ‘exhausted’ T cells, provide a beacon of hope. Both prescription medications and natural compounds are proving valuable in these endeavors. The journey of immunotherapy exemplifies the intricacies of cancer treatment: the road is winding, but every turn brings novel insights and potential solutions. The future holds promise as researchers and clinicians refine the applications of immunotherapy, determined to maximize its benefits for all patients.
References:
Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021 Mar 1;33(3):127-148.
