Introduction
Immunotherapy is considered a leading and hopeful treatment method for cancer patients, stemming from the observation that cancer cells can evade destruction by the immune system, leading to its development. Epidemiologists forecast around 3.4 million new cancer diagnoses in the European Union (EU) and European Free Trade Association (EFTA) nations, along with 1.9 million in the USA, potentially resulting in approximately 1.7 million and 410 thousand deaths annually by 2040, respectively.
In the last ten years, there has been a significant surge in the advancement and application of immunotherapy treatments. As medical professionals gain more experience with these treatments, our comprehension of their accompanying side effects grows. However, compared to the adverse effects on barrier organ systems like the gastrointestinal tract and skin, the impact of immunotherapy on the kidneys, individual nephrons, and kidney function is relatively less documented. The body's reaction to foreign antigens, which are not native to it, is orchestrated by innate and adaptive immune systems.
These two intertwined defense mechanisms are triggered by external pathogens and the "non-self" neo-antigens formed through DNA mutations in cancerous cells. Although this immune vigilance effectively identifies and eliminates cancer cells, as most untreated cancers advance, they inevitably find ways to evade this immune-driven destruction.
What Are the Side Effects of Immunotherapy?
Immunotherapy might induce adverse effects stemming from the heightened activity of the immune system against both cancerous and healthy cells. Variability exists in the occurrence and impact of these effects, influenced by factors such as pre-treatment health, cancer type and stage, immunotherapy type, and dosage. Monitoring for signs of complications is crucial since side effects can manifest unpredictably during and after treatment.
Common side effects include skin reactions at injection sites, like pain, swelling, soreness, redness, itchiness, and rash. Additionally, flu-like symptoms such as fever, chills, weakness, dizziness, nausea, vomiting, muscle or joint aches, fatigue, headache, and respiratory issues may arise. Other potential effects encompass fluid retention leading to swelling and weight gain, heart palpitations, sinus congestion, diarrhea, infection, and organ inflammation. While severe allergic or inflammation-induced reactions are rare, they remain possible with certain immunotherapy types.
What Are the Renal Effects Of Immunotherapy?
Several additional studies corroborate the involvement of immune checkpoint inhibitors in inducing acute kidney injury (AKI). Regarding immune checkpoint inhibitors like pembrolizumab, it has yet to be conclusively established whether the development of autoimmunity in the interstitium arises from de-inhibited T cells, T cell exhaustion, loss of tolerance, activation of memory cells, or a combination of these factors.
Another possibility is that checkpoint-induced interstitial nephritis shares similarities with drug-induced interstitial nephritis, where immunogenic drugs like NSAIDs (non-steroidal anti-inflammatory drugs) and proton pump inhibitors form complexes with proteins, acting as hapten carriers. Hence, a possible connection exists between the reactivation of T cells induced by checkpoint inhibitors and the direct, abnormal harm to podocytes through CD80. This notion gains support from research in the Journal of Nephrology, which examines knockout mice deficient in PD-1 and their development of glomerulonephritis.
The following are the renal effects of different types of immunotherapy:
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Adaptive Cell Transfer - Chimeric antigen receptor T cells (CAR-T) are T cells that have been genetically modified to target tumor cells. Using modified T cells as a therapeutic tool has its roots in the distant past. It was known that solid tumors were infiltrated by at least two types of lymphocytes: (a) lymphokine-activated killer cells, which could be readily expanded from peripheral blood cells (e.g., with IL-2) but demonstrated low, nonspecific anti-tumoral activity, and (b) tumor-infiltrating lymphocytes (TIL), which exhibited high specificity for tumoral cells but proved challenging to expand. Therefore, in the mid-80s, a strategy was developed following numerous attempts to isolate, expand, and genetically engineer TILs.
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Intravesical Bacilli Calmette–Guerin (IVBCG) - IVBCG is an attenuated live vaccine comprising the Bacillus Calmette-Guérin (BCG) strain of Mycobacterium bovis, which received approval in 1990. It is sanctioned for treating (and preventing the recurrence of) non-muscle invasive bladder cancer. Administered intravesically, the vaccine prompts a localized granulomatous response. Besides directly causing cancer cell demise, BCG elicits immune-mediated cytotoxicity involving granulocytes, macrophages, cytotoxic CD8 T cells, and NK cells.
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Vaccines - Cancer vaccines aim to enhance the patient's immune response against tumors to eradicate cancer cells. Although two preventive vaccines against oncogenic viruses (hepatitis B and human papillomaviruses) have gained approval, creating successful therapeutic cancer vaccines has proven difficult.
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Sipuleucel‑T - Sipuleucel-T, sanctioned in 2010, is an autologous cell-based vaccine for addressing asymptomatic metastatic castrate-resistant prostate cancer (mCRPC). The procedure entails extracting antigen-presenting cells (APCs) from the patient's peripheral blood mononuclear cells (PBMCs), which are subsequently cultured with PA2024, a prostate antigen fused with GM-CSF. Subsequently, at least 40 million of the patient's antigen-loaded cells are infused into the individual.
Conclusion
Evidence from case studies and ongoing research strongly suggests a correlation between immunotherapy and renal adverse effects, although the underlying mechanisms have yet to be fully elucidated. As mentioned earlier, most renal adverse effects associated with immunotherapeutics are immune-mediated. Still, the role of the patient's immune system status in determining the likelihood and severity of these adverse effects remains poorly understood. Interestingly, some of the discussed agents vary in isotype class, which could affect both their function and pharmacokinetic profile.
For instance, it has been observed that anti-CTLA-4 monoclonal antibodies (mAbs) may exhibit unique functions based on their specific isotypes, with evidence indicating that ipilimumab may deplete Tregs that overexpress CTLA-4. Additionally, differences in glycosylation patterns among different IgG classes can influence their clearance. Therefore, the isotype class and modification of the agent could impact the likelihood or extent of renal toxicity, although this remains uncertain.
Lastly, greater attention should be directed towards comprehending the effects of both immunotherapy and the treatment employed to manage immunotherapy-induced renal adverse drug reactions (ADR), such as glucocorticoid therapy, on cancer survivorship. For instance, despite abundant evidence indicating improved renal function with glucocorticoids, it remains uncertain how glucocorticoid therapy influences cancer risk and recurrence in patients who have undergone immunotherapy.
