Cancer is a dangerous and dreaded disease that has persisted throughout human history. Though cancer has now emerged as the leading cause of global mortality, rare cancers constitute 230 distinct subtypes with infrequent incidence. Among the known examples are Kaposi’s sarcoma, Merkel cell carcinoma, hepatoblastoma, thymic carcinoma, neuroblastoma, retinoblastoma, and anal cancer, with each exhibiting diverging variations.
Diagnosing and treating rare cancers pose inherent challenges because of their low occurrence rates. Yet, numerous biomedical breakthroughs have seen major advances in treatment. Immunotherapy, targeted therapy, transplant and conventional chemotherapy are the latest advances in therapeutic alternatives for rare cancers. All alternatives have gone through clinical trials, facilitating the remission of tumoursand boosting patients’ overall survival rates.
The National Cancer Institute defines rare cancers as those manifesting in less than 15 cases annually per 100,000 individuals. For instance, rare cancers such as meningiomas and other cancers have extremely low incidence rates of 1.92 and 33.56 per million yearly, respectively.
Unlike common cancers, the subtle nature of rare cancers hampers conventional diagnostic methods such as X-ray imaging and biopsy. This has led to a dearth of research and medical information on their characteristics. However, modern technologies permit medical researchers to detect and study such elusive cancers, thereby advancing their diagnosis, treatment and prognosis.
Despite the therapeutic realm of rare cancers being at an early stage, there is ongoing progress and painstaking research in chemotherapy, targeted therapy, radiotherapy, transplant, surgery and chemotherapy. The discovery of several rare cancer pathways and oncogenic genes has driven the development of anti-tumour drugs. The latest developments can ensure more precise diagnoses, enhanced treatment modalities and improved prognostic capabilities together with major revelations about the pathogenesis of rare cancers.
Immunotherapies to Treat Rare Cancers
The treatment and management of rare cancers have improved immensely during the past decade, especially for immune-based therapies. Immune checkpoint inhibitors, macrophage therapy, chimeric antigen receptor T-cell therapy and neo-antigen-based therapies are the four most popular immune-based therapies. Accordingly, it is imperative to highlight immune-based therapeutic approaches and their present status in treating rare cancers.
Immune-checkpoint inhibitors: Immune checkpoints are immune cell receptors involved in regulating immune homeostasis, in particular the activation of T cells, specific myeloid cells and regulatory cytokines. Since cancer patients possess defective regulatory systems, their immune-checkpoint pathways promote upregulated immune-suppressive functions while downregulating the immune-activating pathways. During the past decade, immune-checkpoint inhibitors, primarily monoclonal antibodies, have achieved prominence by positively influencing the treatment and management of cancer. Immune-checkpoint inhibitors have reportedly produced sustainable responses and are given in metastatic and, recently, in neo-adjuvant and adjuvant settings.
In recent years, the clinical application and use of immunotherapy have recorded mixed results for rare cancers. Significant outcome improvements have occurred in some cancers like Merkel cell carcinoma and pleural/peritoneal mesothelioma. In hepatobiliary cancers and endocrine/adrenal malignancies, the results have been less encouraging.
Macrophage therapy: A new kind of immunotherapy targeting and modulating macrophages is now under investigation. Specialised in host tissues, macrophages undertake varied functions. These include ingesting and degrading debris and dead cells, removing pathogens and regulating inflammatory responses. Macrophages can penetrate and survive within tumour tissues.
Capitalising on this, researchers from the University of Pennsylvania have highlighted a novel macrophage-based therapy. In an individualized approach, monocytes are isolated from patients’ blood, modified with the required antigen-specific chimeric receptor and later given back to these patients. If this approach succeeds, it will be most beneficial for other cancers, specifically those where the tumour microenvironment limits efficacy.
Chimeric antigen receptor T-cell therapy: CAR T-cell therapy is a current form of immunotherapy. T cells are genetically modified to display chimeric receptors that encode an antigen-specific single-chain variable fragment along with several stimulatory molecules. On administration, the modified T cells move to and recognise cancer cells in an HLA (human leukocyte antigens) independent manner. To date, the collective data reveals that CAR T-cell therapy is effective when treating some rare cancers while its efficacy is still under evaluationfor others via clinical trials.
Neo-antigen-based therapies: Neo-antigens represent tumour-cell-specific proteins derived from mutations in protein-coding regions of DNA through acquired mutations, gene rearrangement and alternative splicing. In most tumours without any viral aetiology, tumour neo-antigens may emerge from varied non-synonymous genetic alterations. These include single-nucleotide variants, gene fusions, insertions and deletions, structural variants and frameshift mutations. Studies have indicated the feasibility and effectiveness of neo-antigen-targeted cancer vaccines on murine tumour models that include oesophageal squamous cell carcinoma, sarcoma and glioma.c
Additional Alternatives and Advances in Targeted Therapies
Apart from the above, there are other advances in targeted therapies for rare cancers such as:
Monoclonal antibodies: Derived from a single cell, these antibodies can bind to specific antigens. As these antibodies can differentiate between tumour cells and normal ones, they are safe and effective.
Oncolytic viruses: These are genetically modified viruses that target cancer cells and trigger immune response.
Bite Therapy - The modular nature of BiTE technology facilitates the generation of molecules against tumor-specific antigens, allowing off-the-shelf immuno-oncotherapy.
Imaging and radiomics: These technologies help in characterising tumours, assessing their size and location and monitoring the treatment response.
Computational methods and bioinformatics tools: These help in integrating and analysing large-scale omics data. Machine learning technologies can assist in pinpointing patterns and predicting outcomes while facilitating decision-making.
Moreover, surgery, chemotherapy and radiotherapy or a multidisciplinary mix of therapies can be deployed. While conventional chemotherapy has a 30% success rate, targeted therapies can be up to 80% effective in cancer care. Surgery is most effective in the early stages of cancer. While chemotherapy can curb morbidity and mortality, it could also damage the healthy cells. Similarly, radiation therapy (or radiotherapy) could damage healthy cells and organs but is useful for shrinking tumours and killing cancer cells. Radiation therapy may be administered before, during or after other treatments.
However, the type of treatment a patient receives will be decided by the kind of cancer detected and its stage of advancement. Meanwhile, there are ongoing efforts to enhance the efficiency, precision and cost-effectiveness of various therapies for rare cancers.The success of these efforts will help in early diagnosis, timely treatment and mitigation or cessation of malignant progression of rare cancers.