Solid tumours present significant challenges in cancer treatment due to their diverse nature, aggressiveness, and resistance to standard therapies. Recently, immunotherapy has emerged as a promising strategy for combating some solid tumours by harnessing the body’s immune system to identify and destroy cancerous cells. However, immunotherapy remains more effective for haematologic tumours than for solid tumours in view of the immunosuppressive microenvironment generated by these malignancies. Overcoming resistance to immunotherapy necessitates a comprehensive strategy targeting both intrinsic tumour factors and external influences.
Unlike conventional treatments such as chemotherapy and radiation, which directly target tumours, immunotherapy aims to modulate the immune response to enhance tumour recognition and elimination. The idea of using the immune system to fight cancer has roots dating back over a century, with early observations of tumour regression and immune responses in cancer patients. Notably, significant progress in understanding the immune system’s role in cancer occurred in the late 20th Century, leading to milestones like the discovery of immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), along with its ligand PD-L1, as well as the development
of monoclonal antibodies targeting these checkpoints.
Advancements in immune checkpoint inhibitors and other immunotherapeutic agents have transformed the treatment landscape for various solid tumours, resulting in durable responses and improved survival rates in some patients. Immunotherapy has shown effectiveness across multiple tumour types, including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Ongoing research aims to uncover new immunotherapeutic targets and combination strategies for patients with advanced or treatment-resistant tumours.
Mechanisms of action
Immune checkpoint blockade: One of the extensively researched strategies in immunotherapy is immune checkpoint blockade, which seeks to unleash the immune system’s capacity to identify and eliminate cancer cells. Crucial checkpoint molecules like CTLA-4, PD-1, and PD-L1, are the primary targets of these therapies, governing T-cell activation and immune responses.
Inhibitors of CTLA-4, such as ipilimumab, function by obstructing the inhibitory signals transmitted by CTLA-4, thereby amplifying T-cell activation and proliferation within the tumour microenvironment (TME). Similarly, inhibitors of PD-1/PD-L1 disrupt the interaction between PD-1 on T-cells and PD-L1 on tumour cells or immune cells, thus preventing immune suppression and fostering anti-tumour activity.
Adoptive cell therapy (ACT): An alternative avenue in immunotherapy is ACT, which seeks to enhance the immune response by introducing patients to immune cells that have been expanded or genetically modified ex vivo. Particularly noteworthy is chimeric antigen receptor (CAR) T-cell therapy, which has exhibited remarkable effectiveness in haematologic malignancies and is under investigation for solid tumours. CAR T-cells are engineered to harbour synthetic receptors designed to target tumour-specific antigens, enabling precise identification and elimination of cancer cells.
Tumour-infiltrating lymphocytes (TILs): TILs present another promising strategy. These lymphocytes are those that have migrated into the TME and demonstrate anti-tumour activity. TIL therapy entails extracting TILs from tumour tissue, expanding them ex
vivo, and reintroducing them into the patient, frequently alongside lymphodepleting chemotherapy and interleukin-2 (IL-2) treatment.
Cancer vaccines: Cancer vaccines offer a proactive strategy to activate the immune system against specific antigens found in tumours. These vaccines may consist of various components such as whole tumour cells, tumour antigens, dendritic cells loaded with tumour antigens, or nucleic acid-based vaccines encoding tumour-associated antigens. By initiating an immune response and training the immune system to identify and combat tumour cells, cancer vaccines hold potential for both preventive measures and therapeutic interventions.
Cytokine therapy: Cytokines serve as signalling molecules that regulate immune cell function and inflammation. Among them, IL-2 and interferon-alpha (IFN-α) have been utilised in cancer treatment. IL-2 prompts the proliferation and activation of T-cells and natural killer (NK) cells, bolstering anti-tumour immunity. Conversely, IFN-α exerts anti-proliferative and immunomodulatory effects, proving beneficial in certain solid tumours like melanoma and RCC.
Immunotherapy in specific solid tumour types
Immunotherapy has proven to be highly effective in treating a wide range of solid tumour types, and is being applied in the treatment of some of the most common solid tumours. Melanoma stood out as one of the initial solid tumours to exhibit notable responses to immunotherapy, particularly with immune checkpoint inhibitors.
Medications aimed at CTLA-4 (for instance, ipilimumab) and PD-1 (such as pembrolizumab and nivolumab) have established themselves as standard treatments for advanced melanoma, resulting in lasting responses and better overall survival rates. While combination therapies like ipilimumab plus nivolumab have elevated response rates even further, they may also heighten the likelihood of immune-related adverse events.
Immunotherapy has also emerged as a promising treatment avenue for NSCLC, especially in patients grappling with advanced or metastatic stages of the disease. PD-1/PD-L1 inhibitors like pembrolizumab, atezolizumab, and nivolumab have showcased effectiveness either as standalone treatments or when combined with chemotherapy, serving as options for first-line or subsequent-line therapies.
In RCC, immune checkpoint inhibitors aimed at PD-1/PD-L1 and CTLA-4 have displayed substantial clinical advantages, especially for individuals confronting advanced or metastatic stages of the disease. Pembrolizumab, nivolumab, and ipilimumab stand out as immunotherapy options endorsed for RCC, either as standalone treatments or as part of combination protocols. These interventions have showcased enduring responses and enhanced survival outcomes in contrast to conventional targeted therapies like tyrosine kinase inhibitors (TKIs).
Immunotherapy has established itself as a fundamental component of managing advanced or metastatic bladder cancer, especially for individuals who have experienced progression following platinum-based chemotherapy.
PD-1/PD-L1 inhibitors like pembrolizumab, atezolizumab, and nivolumab have exhibited effectiveness and sustained responses under these circumstances. Moreover, researchers are exploring immune checkpoint inhibitors as supplementary or preoperative therapies in localised bladder cancer, with the goal of enhancing outcomes in the perioperative phase.
Immunotherapy has also demonstrated potential in addressing head and neck squamous cell carcinoma (HNSCC), both independently and alongside chemotherapy or targeted therapies. Although immunotherapy has exhibited restricted effectiveness when used alone in colorectal cancer, especially in microsatellite stable tumours, it has demonstrated potential in a subgroup of patients with microsatellite instability-high (MSI-H), or mismatch repair-deficient (dMMR) tumours.
Immunotherapy has displayed potential in specific subsets of breast cancer too, notably in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-negative disease. Although immune checkpoint inhibitors have shown restricted effectiveness as standalone treatments in unselected TNBC patients, ongoing investigations are concentrating on pinpointing biomarkers and devising combination strategies to amplify responses. Moreover, researchers are exploring the integration of immunotherapy with chemotherapy or targeted agents in TNBC and other subtypes to enhance treatment outcomes.
Gastrointestinal stromal tumors (GISTs) are conventionally managed through surgery and targeted therapy like imatinib, and immunotherapy’s effectiveness in this tumour category has been somewhat restricted. However, PD-1 inhibitors such as pembrolizumab and nivolumab have exhibited modest efficacy in some patients with advanced or metastatic GIST, particularly those showcasing a deficient dMMR phenotype.
Immunotherapy has emerged as a promising treatment avenue for hepatocellular carcinoma (HCC), especially for patients who have experienced disease progression on sorafenib or other systemic treatments. PD-1 inhibitors like nivolumab and pembrolizumab have showcased effectiveness and tolerability in advanced HCC, and ongoing clinical trials are exploring combination approaches that integrate immune checkpoint inhibitors with targeted therapies or other immunotherapeutic agents.
Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge in terms of treatment options, including immunotherapy. While immune checkpoint inhibitors have demonstrated restricted efficacy as standalone treatments in PDAC, ongoing investigations prioritise the identification of biomarkers and combination approaches to bolster responses.
Clinical trials are actively exploring combination regimens that integrate immunotherapy with chemotherapy, targeted therapy, or other immunotherapeutic modalities, aiming to ameliorate outcomes for patients with this aggressive malignancy.
For ovarian cancer, immunotherapy has demonstrated modest efficacy, especially in patient subsets exhibiting high tumour mutational burden (TMB) or DNA repair pathway defects. Immune checkpoint inhibitors like pembrolizumab and nivolumab have shown effectiveness in some patients with recurrent or refractory ovarian cancer, and ongoing trials are investigating combination therapies that integrate immunotherapy with chemotherapy or targeted agents.
Finally, although sarcomas are conventionally managed with surgery, radiation therapy, and chemotherapy, immunotherapy has exhibited limited effectiveness in certain subtypes. Immune checkpoint inhibitors have shown some activity in select groups of patients with advanced or metastatic sarcomas, particularly those with specific histologic subtypes or molecular alterations.
Biomarkers for patient selection and response prediction
Biomarkers play a crucial role in guiding patient selection for immunotherapy and predicting treatment response. PD-L1 expression on tumour cells or immune cells within the TME has emerged as a predictive biomarker for response to PD-1/PD-L1 inhibitors in various solid tumours.
High PD-L1 expression levels have been associated with improved response rates and survival outcomes in certain cancers, such as NSCLC and urothelial carcinoma. However, PD-L1 expression alone is not sufficient to reliably predict response, and its utility may vary depending on the tumour type, assay methodology, and treatment context.
TMB refers to the total number of somatic mutations within the tumour genome and has been proposed as a biomarker for response to immune checkpoint inhibitors. High TMB is thought to increase the likelihood of neoantigen formation and enhance tumour immunogenicity, leading to improved responses to immunotherapy. TMB assessment using next-generation sequencing or other genomic profiling techniques is being investigated as a predictive biomarker in various solid tumours, including melanoma, NSCLC, and some forms of colorectal cancer.
MSI and dMMR deficiency result in a hypermutated phenotype characterised by widespread genomic instability. These molecular alterations are associated with increased TMB and enhanced tumour immunogenicity, making MSI-H dMMR tumours particularly sensitive to immune checkpoint inhibitors.
In addition to PD-L1 expression, TMB, and MSI/dMMR status, ongoing research is exploring other biomarkers to improve patient selection and response prediction in immunotherapy. These include markers of immune infiltration (eg, tumour-infiltrating lymphocytes), immune gene expression signatures, tumour-specific antigens, and host factors (eg, gut microbiota composition). Integrating multiple biomarkers into predictive models may enhance their accuracy and utility in guiding treatment decisions.
Despite the promise of biomarker-driven immunotherapy, several challenges and limitations need to
be addressed. These include variability in assay performance and interpretation, intratumoural heterogeneity, dynamic changes in biomarker expression over time, and the lack of standardised cut-off values for biomarker positivity. Additionally, not all patients with high levels of a specific biomarker will respond to immunotherapy, highlighting the need for ongoing research to identify additional predictive markers and improve patient stratification strategies.
Resistance mechanisms
Resistance to immunotherapy remains a significant challenge in the treatment of solid tumours. Tumours can evade immune surveillance by upregulating alternative immune checkpoint pathways or inducing immunosuppressive signals within the TME.
For example, upregulation of alternative checkpoint molecules, such as TIM-3, LAG-3, and TIGIT, can contribute to immune evasion and resistance to PD-1/PD-L1 blockade. Additionally, factors such as stromal cell-derived cytokines, regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs), and metabolic reprogramming can create an immunosuppressive milieu that hinders anti-tumour immunity.
Intrinsic features of tumour cells, including genetic alterations, epigenetic modifications, and phenotypic plasticity, can also confer resistance to immunotherapy. Tumour cells may develop mechanisms to downregulate antigen presentation, impair T-cell trafficking and infiltration, or evade immune recognition through loss of tumour-associated antigens or major histocompatibility complex expression. Additionally, alterations in signalling pathways (eg, MAPK, PI3K/AKT) and resistance to apoptosis or senescence may contribute to immune evasion and treatment resistance.
The TME plays a critical role in modulating immune responses and shaping treatment outcomes. Tumours can manipulate the TME to create an immunosuppressive niche characterised by hypoxia, acidosis, nutrient deprivation, and extracellular matrix remodelling. Immune cells within the TME, such as tumour-associated macrophages, dendritic cells, and regulatory B-cells, can exert immunosuppressive effects and promote tumour progression. Additionally, the physical barriers posed by the tumour stroma and extracellular matrix can limit T-cell infiltration and immune cell access to tumour cells.
Strategies to overcome resistance
Combination therapies, addressing complementary pathways or immune evasion mechanisms have demonstrated potential in both preclinical and clinical settings as strategies to overcome resistance. For instance, merging immune checkpoint inhibitors with agents that target alternative checkpoint pathways or modulate the TME, like anti-angiogenic agents, cytokine therapy, or radiation therapy, could strengthen anti-tumour immune responses and surmount resistance.
Moreover, strategies to remodel the TME, such as targeting immunosuppressive cells or enhancing T-cell trafficking and function, are under exploration to enhance treatment outcomes.
Personalised medicine approaches, including biomarker-guided therapy selection and adaptive treatment strategies, hold promise in identifying patients primed to benefit most from immunotherapy, optimising treatment efficacy.
Biomarkers predictive of immunotherapy response, such as PD-L1 expression, TMB, MSI/dMMR status, and immune gene signatures, offer guidance in treatment decisions and patient categorisation. Furthermore, real-time monitoring of treatment response and adapting therapy based on evolving tumour dynamics and immune responses could help overcome resistance and enhance long-term outcomes.
Adverse events and management
Immunotherapy has revolutionised cancer treatment but is associated with unique adverse events known as immune-related adverse events (irAEs). These irAEs can affect multiple organ systems and vary in severity from mild-to-life-threatening. Common irAEs include dermatologic toxicities (rash, pruritus), gastrointestinal toxicities (diarrhoea, colitis), hepatic toxicities (elevated liver enzymes), endocrine toxicities (thyroid dysfunction, hypophysitis), pulmonary toxicities (pneumonitis), and others. These adverse events arise from dysregulated immune activation and can occur at any time during or after treatment with immunotherapy.
Prompt recognition and grading of irAEs are essential for early intervention and management. Healthcare providers should have a high index of suspicion for irAEs and monitor patients closely for signs and symptoms suggestive of immune toxicity. Common assessment tools such as the Common Terminology Criteria for Adverse Events and the Immune-related Response Criteria can help standardise the grading and reporting of irAEs.
The management of irAEs depends on their severity and specific organ involvement. Mild-to-moderate irAEs may be managed conservatively with supportive care measures, such as topical or systemic corticosteroids, antidiarrhoeal agents, or anti-inflammatory medications. Severe or life-threatening irAEs may require treatment discontinuation, high-dose corticosteroids, immunosuppressive agents, or other interventions to control inflammation and prevent complications.
Managing irAEs often requires a multidisciplinary approach involving oncologists, dermatologists, gastroenterologists, endocrinologists, pulmonologists, and other specialists. Close communication and collaboration among healthcare providers are essential for timely diagnosis, treatment, and monitoring of irAEs. Patient education and counselling about the potential risks and benefits of immunotherapy and the importance of reporting symptoms promptly are also crucial for optimal care.
While many irAEs resolve with appropriate management, some patients may experience long-term or chronic sequelae, such as hypothyroidism, adrenal insufficiency, or autoimmune disorders. Long-term monitoring and follow-up care are essential to detect and manage late-onset irAEs and optimise patient outcomes. Survivorship programmes and supportive care services can help address the physical, emotional, and psychosocial needs of cancer survivors and mitigate the long-term effects of cancer treatment.
Conclusion
Immunotherapy has emerged as a transformative approach in the management of solid tumours, offering new hope for patients with advanced or refractory disease. Key advancements, including immune checkpoint inhibitors, adoptive cell therapy, cancer vaccines, and targeted immunotherapies have expanded the therapeutic arsenal and reshaped the treatment landscape across a wide range of solid tumour types.
However, despite the remarkable progress made in the field of immunotherapy, several challenges remain. Immunotherapy resistance, immune-related adverse events, biomarker identification, and treatment optimisation are areas of ongoing research and clinical investigation. Personalised medicine approaches, combination therapies, novel immunotherapy targets, and strategies to modulate the TME are being explored to enhance treatment responses and overcome resistance. With continued research and innovation, immunotherapy holds the potential to transform the way clinicians understand, diagnose, and treat cancer, ultimately leading to better outcomes and a brighter future for cancer patients worldwide.
References available on request
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