Introduction
Immunotherapies like immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have transformed cancer treatment, offering new hope to patients previously deemed incurable. Despite their promise, many patients experience primary and secondary resistance to single-agent immunotherapy, leading to treatment failures. Long-term benefits are observed in only a minority of patients.
The primary immunotherapies for solid cancers continue to be the approved Immune Checkpoint Inhibitors (ICBs), which include antibodies targeting programmed cell death 1 (PD1), PD1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Recently, adoptive cell therapy (ACT), such as chimeric antigen receptor-engineered T (CAR-T) cells, has emerged as a potent treatment for haematological malignancies. While ICBs work by restoring suppressed pre-existing anti-cancer immunity, CAR-T cells operate differently by bypassing antigen presentation, T cell priming, and activation processes, enabling direct attacks on cancer cells.
One approach to enhance immunotherapy response is combining agents that employ diverse mechanisms of action and target multiple resistance pathways.
Combinations of chemotherapy and immunotherapy
Currently, several chemotherapy agents have been approved in conjunction with immunotherapy drugs, as indicated previously. The possible mechanisms of action include:
1. Tumour debulking by chemotherapy: This reduces the production of immunosuppressive factors and decreases the number of cancer cells requiring elimination by drugs.
2. Immunogenic cell death (ICD): Chemotherapy induces a form of regulated cell death in immunocompetent individuals, which can potentiate immunotherapy.
3. Increase in antigenicity of cancer cells: Chemotherapy directly destroys cancer cells or induces apoptosis. After cell death, antigen-presenting cells engulf the dying tumour cells and present them to immune cells.
4. Depletion of immunosuppressive cells: Chemotherapy drugs like gemcitabine and platinums alter the tumour microenvironment, promoting the development of immune cells that support anticancer immunity.
5. Restoration of chemosensitivity
Combination of radiation therapy with immunotherapy
The concept of stimulating anti-cancer immunity through radiotherapy (RT) was initially observed in case reports where local RT led to the regression of distant untreated tumours, termed the Abscopal effect. Proposed mechanisms include:
1. Enhancement of anticancer immunity by RT: Radiation exposes tumour antigens to immune cells.
2. Downregulation of CD47 expression: CD47 serves as a “Do not eat me” signal on tumour cells to immune cells.
3. Increased antigenicity due to reactive oxygen species.
The first documented benefits of combining RT with immunotherapy were observed in melanoma. In lung cancer, patients previously treated with radiation showed improved responses to immunotherapy.
However, the benefits of combining immunotherapy and radiation across different diseases remain controversial due to radiation’s potential to also kill essential immune cells.
Combination of targeted therapy with immunotherapy
Driver mutations in cancers propel their growth, and targeting these mutations often yields superior results compared to chemotherapy. For instance, in lung cancer patients with EGFR mutations, targeted therapy achieves a response rate of 80 per cent, whereas chemotherapy typically yields a 30 per cent response. Combining immunotherapy with targeted therapies has shown significant benefits, leveraging mechanisms akin to those of chemotherapy and radiation. Additionally, targeted therapies exert profound effects on the tumour microenvironment, further enhancing therapeutic outcomes. These advancements are particularly promising in kidney cancers, hepatocellular carcinomas, and melanomas. Ongoing research is also exploring the potential of targeted therapies in hematologic cancers.
Adoptive cell therapy
Cellular immunotherapy involves the transfer of immune cells, either autologous (from the patient) or allogeneic (from a donor), into cancer patients to stimulate an anti-cancer immune response. Immune cells are extracted, modified, and cultured in vitro before being reintroduced into the patient. This approach paved the way for Chimeric Antigen Receptor T-cell therapy (CAR-T), initially employed in melanoma to enhance the killing of melanoma cells by engineered T cells. CAR-T therapy is still under development for use in solid cancers.
Recent studies are investigating the combination of CAR-T therapy with immunotherapy drugs to potentially enhance treatment efficacy.
Virotherapy and Immunotherapy
Cancer cell vaccines utilising adenoviruses, herpes viruses, and coxsackie viruses are currently in clinical development. These viruses have been genetically modified with cancer-tropic genes to penetrate cancer cells and induce their destruction. To date, three oncolytic viruses (OVs) have been approved and utilized in clinical settings: Rigvir (a picornavirus), H101 or Oncorine (an adenovirus), and talimogene laherparepvec, also known as T-vec (a herpes simplex-1 virus encoding GM-CSF). These OVs operate through direct action on cancer cells, as well as by activating the immune system and triggering apoptosis.
Therapeutic cancer vaccine
A cancer vaccine is a form of targeted cancer immunotherapy designed to stimulate anti-cancer immunity by presenting cancer antigens through various methods such as proteins, RNA, DNA, viral or bacterial vectors, cells, or other means. Currently, these vaccines exhibit an efficacy of approximately 5 per cent. They are administered to patients whose immune systems have become tolerant to cancer or in cases where cancers have developed or established an immunosuppressive tumour microenvironment (TME) that impedes anti-cancer immune responses.
Conclusion
The field of Cancer Immunotherapies is poised for exciting advancements. By combining various approaches—immunotherapy with chemotherapy, radiation, targeted therapies, CAR-T cells, viruses, and cancer vaccines—clinicians will encounter numerous opportunities and challenges. The era of ‘one size fits all’ strategies is fading away, giving rise to personalised cancer therapies that are not only thriving but also here to stay.