In a healthy individual, the immune system responds to “foreign” cells (such as cancer) by attacking and eliminating them. Unfortunately, cancer cells have their own strategies for evading this immune response, leading to further proliferation and potential metastasis. The traditional course of action is to treat the disease using surgery, chemotherapy, or radiotherapy (or some combination of these). However, many patients simply do not respond to these established therapies.
Immunotherapy – a type of biological therapy – is a treatment strategy focused on harnessing the power of the patient’s immune system to attack cancer and stunt its development. It shows great promise as a bespoke therapy for cancers that do not respond to traditional treatments and could improve quality of life for many patients.
Immunotherapies
A wide range of immunotherapy types are now available, but the most successful to date have been checkpoint inhibitors, CAR T-cell therapy and cancer vaccines.
Checkpoint inhibitors
Immune checkpoint inhibitors are drugs that are able to block T cell activation and regulate hyperactivation of the immune system. The most well-known examples are antibodies that block the cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death 1 (PD-1) proteins.
These drugs are used to treat melanoma, renal cell carcinomas, colorectal cancers, non-small cell lung cancer, head and neck cancer, cervical cancer, endometrial cancer, bladder cancer and breast cancer – with more cancer types on the horizon.
In 2022, a small-scale trial made headlines when all 12 participants with mismatch repair-deficient, locally advanced rectal cancer had a complete clinical response to the programmed death (PD-1) blockade agent, dostarlimab. Approximately 5-10% of rectal adenocarcinomas are mismatch repair-deficient, and these tumours do not respond well to chemotherapy regimens, including neoadjuvant chemotherapy. The trial participants exhibited no adverse events of grade 3 or higher and showed no progression or recurrence of cancer during follow-up.
CAR T-cell therapy
Chimeric antigen receptor (CAR) T-cell therapy – otherwise known as T-cell transfer therapy – is a specialised immunotherapy in which changes are made to the genes of a patient’s T-cells to increase their efficiency in recognising and destroying cancer.
Once these tweaks have been made in the lab, the T-cells are grown in batches and put back into the body via an intravenous drip. CAR T-cell therapy is currently used to treat children with some forms of leukaemia, and in adults with lymphoma.
CAR T-cell therapy is not as widely used as checkpoint inhibitors, but there are many examples of where it has been useful in the treatment of patients. Overall, six CAR T-cell therapies have been approved by the FDA, covering blood cancers such as lymphomas, some forms of leukaemia, and multiple myeloma. In a study looking at patients in remission from chronic lymphocytic leukaemia, CAR T cells remained detectable for more than a decade after initial infusion.
Cancer vaccines
There are two types of cancer vaccines: prophylactic and therapeutic. Prophylactic vaccines are more similar to a traditional vaccine and are used to prevent infection by an oncogenic virus. One common example is the human papillomavirus vaccine against cervical cancer.
Therapeutic vaccines harness tumour-associated antigens to help the immune system eliminate cancer cells. Non-cancerous cells are protected from this attack as they either do not display these antigens or do not possess the antigens in high enough numbers to be targeted.
Other vaccines use proteins or peptides from cancer cells to stimulate an immune response to the cancer. Some vaccines are made with the DNA or RNA of targeted cancer cells and are injected into the body to improve the immune response to tumour cells. Whole cell vaccines use the entire cancer cell and are genetically modified to express cytokines, chemokines, or other molecules that stimulate an immune response to the injected irradiated tumour cells. Using the whole cell to generate a vaccine ensures patients are vaccinated with cells containing the same antigens that their tumour expresses. Vaccines made from allogeneic cells use several cell lines derived from different tumours in the vaccine, so there is a better chance the patient’s tumour will share antigens expressed by the vaccine cells.
Cancer genomics in precision oncology
In the past, cancer was defined in terms of the tissue-of-origin – if a cancer originated in the lung, it is lung cancer. With the dawn of tumour sequencing, we now have an insight into the many different subsets of cells within a cancer and how these are defined based on their patterns of genetic alterations.
In the clinic, this has seen us move from treatment determined by the location of the tumour in the body, to considering the molecular patterns present in cancers and treating them accordingly. In clinical trials, we have seen a similar shift towards small, focused patient populations to test treatments, and drugs that are matched to specific mutations in a patient’s cancer. Ultimately, this has led to better responses to treatment.
As a field, we have also become more aware that each cancer is unique to the patient – and that this is based on DNA mutations that cause certain cells to act abnormally. As many as 15% of people with cancer have mutations that make chemotherapy an ineffective option. This is because the mutations cause the cancer cells to have increased resistance to chemotherapy drugs, for example by blocking their ability to enter the cell and destroy the DNA. Therefore, researchers are working to fully understand the genetic makeup of different cancers to help doctors select better treatments that target the specific mutations in each patient’s cancer cells.
NGS and genomic data
NGS data has proven instrumental in developing targeted therapies (drugs that directly attack cancer by altering expression of crucial oncogenes) and immunotherapies in precision oncology. NGS methods and bioinformatics platforms have generated oceans of cancer genomics data which has been used to target aggressive cancers that do not respond, or respond poorly, to conventional treatment options.
NGS was used to obtain massive amounts of genomic data from cancer patients with acute myeloid leukaemia, which later expanded to other solid tumours, and now forms The Cancer Genome Atlas (TCGA). NGS profiles from a host of tumours can assist in the creation of targeted therapies by identifying mutations in signalling pathways and blocking them with existing or novel drugs.
Several onco-immunotherapy drugs have been developed and approved by the FDA in recent years, including pembrolizumab, atezolizumab and pembrolizumab. These are all checkpoint inhibitors that harness monoclonal antibodies (MABs) to mimic natural antibodies and trigger an immune response to certain cancer types, or by bolstering the immune system in mounting an attack on cancer cells.
Genomic screening could help identify those patients most likely to respond to this form of treatment. For example, tumour mutational burden (TMB) is the total number of somatic mutations per coding area of a tumour genome. Tumours with a high TMB are more likely to express neoantigens and induce stronger responses to immune checkpoint inhibitor therapy. Testing for TMB could prove useful in selecting patients for potential treatments and increasing the overall response rate for immunotherapies.
Similarly, immunotherapy could prove useful in cancers with a defective DNA mismatch repair gene. These cancers will often demonstrate microsatellite instability (MSI) – an inconsistent number of nucleotide repeats compared to normal tissue. Following advances in MSI detection technology, it is now possible to identify those patients exhibiting MSI-high tumours who may benefit from targeted immunotherapy.
