Immunotherapies continue to hold promise for the treatment of glioblastoma, a malignant central nervous system tumor. Thus far, success utilizing this approach has been limited. Negative trials with vaccines and immune checkpoint inhibitors have been unable to demonstrate improvement in survival, however, they have provided insights into hurdles which need to be overcome. Ongoing investigations into modulation of the highly suppressed tumor immune microenvironment, direct simulation of the immune system for proinflammatory effect, and the use of cellular therapies will help inform future therapeutic directions.

Prostate cancer (PCa), a leading cause of cancer mortality in men, has experienced a paradigm shift with the rise of immunotherapy. This chapter examines the immunological landscape of PCa and highlights key immunotherapeutic approaches, including cancer vaccines, immune checkpoint inhibitors (ICIs), adoptive cell therapies, and cytokine-based treatments. Emerging innovations, such as oncolytic viruses, neoantigen-based therapies, and bispecific antibodies, are also examined. Challenges like the immunosuppressive tumor microenvironment (TME), limited predictive biomarkers, and immune-related adverse events (irAEs) are addressed, alongside promising combination strategies with androgen deprivation therapy (ADT), radiotherapy, and targeted therapies. Advances in biomarker discovery and artificial intelligence (AI) are emphasized for their role in optimizing personalized immunotherapy. This chapter underscores the need for equitable access to these advancements and concludes with a vision for integrating immunotherapy into standard care, offering durable and transformative outcomes for PCa patients.

Immunotherapeutic approaches have created effective therapy with a manageable toxicity profile as a new treatment approach in a wide variety of cancers, often leading to longer responses and control of disease. In pancreatic cancer, responses to immunotherapy have been difficult to capture. Many obstacles have been identified in the limited efficacy of immunotherapy in pancreatic cancers. The hostile tumor microenvironment plays a large role in therapeutic development of immune-based therapies in pancreatic cancer. The approach to addressing many of these challenges will require a team-based approach to optimize both our understanding of the disease, its microenvironment, and how each component behaves in the development and growth of pancreatic cancer as well as the mechanisms used to best create therapies and combinations of treatment that will have long-standing efficacy for pancreatic cancer patients.

Colorectal cancer (CRC) is a growing concern worldwide, particularly affecting younger populations in recent years. The progression of CRC involves diverse molecular pathways, each contributing to how the tumor behaves and responds to treatment. The immune system is crucial in detecting and destroying cancer cells, but tumors can avoid immune destruction through various strategies, such as altering antigen expression or reshaping their environment to suppress immune activity. These escape mechanisms have prompted the development of immunotherapy, which has significantly improved outcomes for patients with specific genetic profiles like microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). Drugs such as pembrolizumab, nivolumab, and others have demonstrated notable clinical benefits in these populations. Research is now expanding to evaluate immunotherapy in earlier stages of disease and in combination with other treatments like chemoradiation, even in patients without traditional predictive biomarkers. Ongoing studies are also exploring novel immune targets and combinations to enhance effectiveness and broaden access to these therapies. Understanding the interaction between tumor biology and the immune system is essential for advancing personalized care in CRC.

Breast cancer (BC) is the most prevalent malignancy among women in the United States, affecting approximately 13% of the female population. While advancements in treatment strategies have improved survival rates, significant challenges remain due to tumor heterogeneity, metastatic progression, and acquired resistance to therapy. Recent studies have highlighted the potential of immunotherapy in managing various solid tumors, including BC. This growing interest stems from increasing recognition of the immune system's role in both normal breast tissue and BC development, leading to extensive clinical investigations into BC immunotherapy and its tumor immune landscape. Despite its promise, immunotherapy for BC faces hurdles such as low tumor immunogenicity, inadequate T-cell infiltration, and a highly immunosuppressive tumor microenvironment (TME), which limit its efficacy. Among the available approaches, PD-1/PD-L1 inhibitors have shown clinical benefit in a subset of metastatic BC patients, particularly those with PD-L1-positive tumors, triple-negative BC (TNBC), or high tumor-infiltrating lymphocyte (TIL) levels. Notably, atezolizumab and pembrolizumab have demonstrated durable responses in metastatic TNBC, underscoring their therapeutic potential. Current research is focused on developing combination immunotherapy strategies that can overcome resistance, enhance response rates, and convert non-responders to therapy-sensitive cases. A key area of investigation involves identifying biomarkers that can predict immunotherapy responsiveness, guide salvage therapy in progressive disease, and optimize personalized treatment combinations. This review explores the latest advancements and future directions in BC immunotherapy, including novel combination strategies with vaccines and chemotherapeutics aimed at improving treatment efficacy and patient survival outcomes.

There have been tremendous advancements in immunotherapy approaches for patients with renal cell carcinoma (RCC) from the initial interleukin-2 era to the current immune checkpoint inhibitor (ICI) combinations. Several ICI-based therapies have greatly improved outcomes for patients with RCC with the potential for durable responses for a subset of patients. In this chapter, we review the data of key frontline ICI-based combinations for RCC in the metastatic setting and recent data on adjuvant immunotherapy. We also discuss recent data on the role of immunotherapy rechallenge following prior ICI treatment as well as emerging novel immunotherapy strategies with chimeric antigen receptor (CAR) T and gut microbiome interventions. Lastly, we highlight a multidisciplinary team-based approach for patients with RCC treated with ICI including management of immune-related adverse events as well as potential role of cytoreductive nephrectomy in an evolving treatment landscape.

Immunotherapy has reshaped the treatment landscape of several malignancies, including breast cancer. While historically considered less immunogenic, breast cancer-particularly the triple-negative subtype (TNBC)-has demonstrated responsiveness to immune checkpoint inhibitors (ICIs). TNBC is characterized by higher tumor mutational burden, elevated PD-L1 expression, and increased tumor-infiltrating lymphocytes, making it a leading focus of immunotherapy development. In metastatic TNBC with PD-L1 expression, trials such as KEYNOTE-355 have shown improvements in progression-free and overall survival with the addition of the ICI, pembrolizumab to chemotherapy, leading to regulatory approval. In early-stage TNBC, KEYNOTE-522 established a neoadjuvant chemotherapy plus ICI as the standard of care for stage II and III tumors. This was based on improved pathologic complete response and event-free survival in this pivotal clinical trial regardless of PD-L1 expression. ICIs in other subtypes, such as HER2-positive and hormone receptor-positive/HER2-negative disease, remain under active investigation. Ongoing studies are also exploring novel strategies including dual immune checkpoint blockade, cellular therapies (e.g., CAR-T, TILs), cancer vaccines, and rational combinations with targeted agents and antibody-drug conjugates (ADCs). Biomarkers such as PD-L1, tumor mutational burden, immune gene signatures, and the gut microbiome are being evaluated to refine patient selection and predict response. Additionally, effective management of immune-related toxicities is critical, particularly in curative-intent settings. As the role of immunotherapy expands, a multidisciplinary, biomarker-driven approach will be essential to optimize outcomes and broaden its applicability across breast cancer subtypes.

Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) makes up the large majority of lung cancer diagnoses. After the discovery of immune modulators or immunotherapy, treatments that could utilize the patient's own immune system to target malignant cells, the landscape of lung cancer treatment, NSCLC in particular, has greatly evolved with vast improvements in outcomes and survival. Currently, immune checkpoint inhibitors (ICI) have had the greatest impact on the current treatment of non-driver mutated non-small cell lung cancer. Unfortunately, resistance to treatment whether primary or secondary, remains a concern. To overcome resistance, investigators have sought combination immune modulator treatments and have even identified novel agents to utilize, including adoptive cellular therapies, antibody-drug conjugates, and vaccines. Some of these agents have been more successful than others with combination strategies currently leading the way but there are some limitations. Other agents are early in development and will need to await further data before determining the impact on lung cancer treatment. Immunotherapy or immune modulatory agents remain an essential aspect of NSCLC treatment and continue to be the subject of novel research and development.

Cancer immunotherapy is a major advancement in the field. It works by stimulating the patient's immune system to recognize and destroy cancer cells. Several different types of cancer immunotherapies have been developed, such as T-cell therapy, immune checkpoint inhibitors, monoclonal antibodies, cancer vaccines, and many others, which can result in sustainable responses in patients with a wide range of metastatic diseases. Additionally, immunotherapy drugs are being combined with chemotherapy and other targeted therapies to treat a variety of cancer types. Despite the promising results, several challenges remain, such as the almost inevitable immune resistance, drug-related toxicity, and the lack of established and reliable predictive biomarkers to predict toxicity and/or discern a patient's response to immunotherapy. In this chapter, we summarize the mechanisms underlying cancer immunotherapy resistance, especially the contributions of phenotypic plasticity and the underlying non-genetic mechanisms. Furthermore, recent developments in preventing relapses following treatment so that the efficacy of immunotherapy can be improved are also briefly discussed. Finally, the positive impact of an interdisciplinary "Team Medicine" approach to personalize cancer immunotherapy for each patient is highlighted.

Artificial intelligence (AI) and machine learning (ML) are revolutionizing cancer immunotherapy by addressing the complex interplay between cancer and the immune system. This chapter explores how AI technologies enhance immunotherapy development across multiple domains: antibody design, response prediction, biomarker identification, and T-cell target discovery. In therapeutic antibody design, AI improves efficiency through predictive modeling of antibody-antigen interactions, structure prediction tools, generative models that create novel antibody sequences, and developability optimization. Clinical applications include AI-powered systems that predict immunotherapy responses using multi-omics data integration, helping distinguish pseudoprogression from true disease progression. Beyond conventional biomarkers like programmed cell death protein 1, AI enables identification of additional markers including tumor mutational burden, microsatellite instability, immune cell infiltration patterns, and novel genomic alterations. Multi-omics approaches leverage AI to synthesize diverse data types, uncovering complex biomarker signatures that more accurately predict treatment outcomes. For T-cell target identification, next-generation immunoediting platforms like Gritstone's EDGE™ system exemplify AI-powered approaches that precisely identify neoantigens by integrating sequencing technologies with sophisticated prediction algorithms (Table 2.1). These platforms support both personalized and shared antigen approaches to immunotherapy, potentially enhanced through integration with innate immune pathways. Despite remarkable progress, challenges persist in addressing tumor heterogeneity, immune evasion mechanisms, and technical limitations in prediction algorithms. The continued refinement of AI approaches, expansion to diverse cancer types, and integration with complementary therapeutic modalities represent promising future directions. Overall, AI and ML are poised to transform cancer immunotherapy by enabling more precise, effective, and personalized treatment approaches that harness the immune system's power against cancer.