SPOTLIGHT cells. Decades of basic, translational, and clinical research, starting from the recognition of GD2 as a tumor protein in 1984, led to the development of dinutuximab. Recent data demonstrate that the therapeutic antibody is extending lives for many children with high-risk neuroblastoma (476). Since the approval of dinutuximab in 2015, the FDA has approved a second therapeutic, naxitamabgqgk (Danyelza), that works similarly to dinutuximab, for the treatment of patients with neuroblastoma. Current Challenges in Cancer Immunotherapy As described throughout this section, over the past decade, immunotherapeutics have revolutionized the landscape of cancer treatment. However, immunotherapeutics have been successful in treating only a fraction of patients with cancer with several challenges remaining. These include serious and even life-threatening adverse effects; patients who respond initially but develop resistance over time; and the current gaps in our understanding of how to integrate immunotherapies with standard cancer therapies. In this section we outline some of the current limitations and known challenges of cancer immunotherapy. Knowledge Gaps in Predicting Response to Immunotherapy Immunotherapeutics have shown extremely durable responses in certain patients with cancer. To determine if a patient may respond to these therapeutics, clinicians use biomarkers, molecules that can identify certain characteristics of a cell or a tissue. The most common biomarkers currently used to select patients for ICI treatment are the presence of certain surface proteins on cancer cells and the presence of specific molecular characteristics. The presence of a biomarker, for example surface levels of PD-L1 protein, informs the clinician whether a patient might respond to a PD-1/PD-L1 targeted immunotherapy, such as pembrolizumab. However, one concern is that levels of these biomarkers are not always consistent with one study finding that levels of PD-L1 change over time and are not the most reliable biomarker for anti-PD-1 therapies (477). Another major challenge in cancer immunology biomarker research is the lack of diversity in genetic databases and underrepresentation of individuals of non-European genetic ancestry (478). As a result, gaps remain in our understanding of the ancestry-related differences of tumors and the immune system, which are key contributing factors in determining efficacy of cancer immunotherapies. As one example, one study found that Black individuals can be misclassified as having a cancer with a high tumor mutational burden (TMB-h), a biomarker used in some cases to select patients for treatment with certain immunotherapeutics, including pembrolizumab. Further, the study found that patients of African ancestry classified as h-TMB did not respond to pembrolizumab because of this misclassification (479). These findings illustrate the importance of increasing diversity of genetic databases to include more individuals from non-European ancestries. Like other anticancer therapeutics, one concern after ICI treatment is the possibility of cancer recurrence. Recurrence or relapse of metastatic disease after initial response may occur because of acquired resistance, wherein a cancer no longer responds to the therapeutic (see Sidebar 35, p. 87). The underlying mechanism of acquired resistance is multifactorial and is influenced by both extrinsic and intrinsic factors (480). Extrinsic factors include the tumor microenvironment (see Tumor Microenvironment, p. 35), and the presence of certain inhibitory immune cells that can change or accumulate over time. Intrinsic factors that lead to acquired resistance of a tumor include the downregulation of certain proteins on the surface of cancer cells that are required for the therapeutic to work. Identifying biomarkers that predict cancer recurrence is an area of active research. Utilization of combination therapy and strategies that target the tumor microenvironment are among the ways to overcome resistance and is another area of extensive investigation (see A New Age of Therapeutic Combinations, p. 130). Finally, when a patient should cease receiving treatment with an ICI has not been well defined. This is because traditional endpoints, such as overall survival, progression free survival, and overall response rate, are not well-matched for assessment of ICIs (481,482). For instance, when measuring the overall response rate of a tumor to therapy, clinicians often examine tumor size before and after a treatment. Tumor shrinkage after therapy corresponds to a higher overall response rate. However, with ICI treatment, tumors often continue to grow before they shrink (e.g., pseudoprogression), which may initially be perceived as a lack of response (483). To overcome these limitations, criteria to define endpoints for ICIs have been developed (484); however, validation of these criteria will require large amounts of patientderived data over a long period of time. Continued optimization and research for ICI endpoints must be developed to understand how long patients need to continue treatment. Adverse Effects of Immunotherapy Immunotherapeutics have led to more cancer survivors living through and beyond their cancer, with some patients remaining cancer free for 10 or more years. As the use of immunotherapy becomes more widespread, understanding the immediate and long-term adverse health impact of these therapeutics is crucial to improve health outcomes. Cytokine release syndrome (CRS) is the most common immediate side effect following treatment with CAR T-cell therapy with a reported incidence of 37-93 percent Immunotherapy: Pushing the Frontier of Cancer Medicine AACR Cancer Progress Report 2023 125
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