SPOTLIGHT (453,485,486). CRS can develop within hours or days following infusion and is characterized by an excessive immune reaction that leads to widespread organ dysfunction that can become life-threatening (485). Following CRS, up to 40 percent of CAR T-cell recipients may develop another type of side effect called immune effector cell-associated neurotoxicity syndrome (ICANS), which can lead to neurological symptoms that affect speech, orientation, handwriting, and concentration (487). While alarming, these side effects are often short-lived and readily managed with both corticosteroids and the IL-6R antagonist tocilizumab, approved by FDA to treat CRS in 2017 (488,489). Further evidence demonstrates that once a patient overcomes these symptoms, they do not recur (490). A long-term side effect that has been observed in patients who receive CAR T-cell therapy targeting B-cell malignancies is depletion of normal B cells, called B cell aplasia. This condition arises when CAR T-cell therapy targets CD19, which is expressed not only on cancer cells but also on nonmalignant B cells, meaning that these cells can also be eliminated. B cell aplasia has been reported in 25-38 percent of patients for up to several years after conclusion of the treatment (491,492). Other long-term side effects of CAR T-cell therapy include cytopenias, which are conditions in which there are lower than normal numbers of blood cells. Cytopenias include anemia (low red blood cells), thrombocytopenia (low platelets), and neutropenia (low neutrophils), and can occur in approximately 15 percent of patients with B-cell lymphoma more than three months after CAR T-cell infusion (493-496). Cytopenias persisted in long-term follow-up of 15–22 months in about 16 percent of patients (497). Other reported side effects, including increased risk of infection and malignant transformation of transduced cells are not well understood. Further complicating these findings is the difficulty of attributing these side effects to the treatment or the cancer itself. The development of immune-related adverse events (irAEs), which are side effects from treatment with ICIs, can occur from the beginning of treatment and last well beyond its completion. The likelihood of someone treated with ICIs developing at least one irAE varies between 13.7 percent and 54 percent depending on the type of ICI (498). Although they are often mild, ICI-induced irAEs can develop into more serious conditions that could become irreversible or even fatal (499). Many of these side effects are similar to autoimmune reactions, such as colitis, rash, or arthritis. These side effects have been documented in many organs and tissues (see Figure 20, p. 127). Identification of new biomarkers is vital to better predict if a patient will develop irAEs, as well as to reduce the possibility of these side effects. One promising area is examining whether the levels of certain immune cells in the body are associated with the development of severe irAEs. One study showed that levels of certain types of CD8+ T cells could predict if a patient would develop arthritis following the administration of ICIs (see Sidebar 38, p. 100) (503). The presence of certain immune cells has also been associated with the development of side effects such as colitis, pneumonitis, and thyroiditis (503-505). Biomarkers in the blood could also be used to predict severe irAE, including cytokines such as IL-17, IL-6, and IL-8, all of which are elevated in patients who develop colitis following treatment with ICIs (505,506). As patients treated with ICIs are living longer (507), it is important to note that although oncologists are generally aware of the potential for irAEs, this awareness is not as prevalent among primary care physicians who are a patient’s first point of contact when seeking care. One study found that while 93 percent of physicians recognized the gastrointestinal tract was at risk for developing irAEs, only 57 percent recognized that the cardiovascular system and 67 percent recognized that the renal system was at risk following administration of ICIs (508). With the increased use of immunotherapeutics resulting in improved survival, a better understanding of their long-term and late effects is urgently needed to improve quality of life for patients who receive immunotherapy. Disparities in Access to Immunotherapy Emerging evidence shows that there are disparities in the access to immunotherapeutics, such as ICIs, particularly among racial and ethnic minority groups (see Sidebar 2, p. 17). One study of over 17,000 patients found that counties that were urban, had a higher proportion of Hispanic and Latino populations and higher poverty levels, had slower initiation of ICI therapy after diagnosis (510). The slow uptake of ICI occurred despite a higher density of cancer physicians, which indicates that the disparity was not exclusively due to lack of availability of appropriate care facilities. Treatment of HCC, with immunotherapeutics was lower among both Hispanic and Black patients compared to White patients despite HCC having a higher incidence among Black and Hispanic populations (511, 512). This is especially ICI in combination with chemotherapy increased the risk of cardiotoxicity by 67 percent compared to chemotherapy alone in an analysis of patients with lung cancer across multiple studies (509). AACR Cancer Progress Report 2023 Immunotherapy: Pushing the Frontier of Cancer Medicine 126
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