About Author: Dr Thangarajan Rajkumar is a distinguished medical professional with an exceptional career spanning across various fields. Apart from his role at MedGenome, he is also serving as an Adjunct Professor at IIT Madras, and a Visiting Professor at the Department of Nanosciences & Molecular Medicine at AIMS, Kochi. Dr Rajkumar has achieved numerous accolades, such as being the first qualified Medical Oncologist with a Ph.D. in Basic Science (Molecular Oncology) in India.
For years, the standard therapeutic options for cancer treatment and management have included surgery, radiotherapy, and chemotherapy. In recent times, immunotherapy has emerged as a powerful new ally in the fight against cancer. This innovative approach, emerging over the past two decades, offers patients a new wave of hope. Over the past decade, major developments such as Immune checkpoint blockade (ICB) or Immune checkpoint inhibitors have made a major difference in successfully treating some cancers. In addition, a form of Cell therapy called Chimeric Antigen Receptor – T (CAR-T) cell therapy has shown impressive results in a small group of patients with blood cancers and lymphomas.
Monoclonal antibody for therapy
The first therapeutic monoclonal antibody approved by FDA was Rituximab (1997) used to target CD20 antigen in B-cell malignancies including lymphomas. Subsequently, it was used to treat autoimmune disorders driven by B-cells, like Rheumatoid arthritis. Another monoclonal antibody, Trastuzumab (FDA approved it in 1998) which acts against HER2 protein expressed in breast cancers. The absolute benefit of Trastuzumab is 8% in disease-free survival, which is a major increment.
Subsequently, the antibodies were coupled to a toxic molecule (Antibody Drug Conjugate – ADC), so that the toxic molecule can be selectively delivered to the cancer site. Most of these ADCs are used in metastatic diseases and also in elderly patients. The cost of these ADCs is high.
Immune checkpoint inhibitors [blockade] [ICI OR ICB]
Our immune system is a finely tuned machine which on the one hand helps fight infectious agents, cancers etc., and at the same time is under check to prevent reacting to one’s own antigens, which can lead to autoimmune disease. Among the key controllers of this are the immune checkpoint proteins, including CTLA4 and PD1-PD-L1 system. These proteins help control the immune system from overactivity.
Cancer cells have hijacked these proteins so that they can prevent the T-cell from destroying them. Antibodies developed against CTLA4 (Ipilimumab), against PD1 which is expressed by T-cells (including Pembrolizumab and Nivolumab), and against PD-L1 protein expressed by cancer cells (including Atezolizumab and Durvalumab) help in breaking this tumour resistance and promote cell killing by the activated T-cells.
“Cancer Immunotherapy is now an essential component of therapy in several common cancers.”
The immune checkpoint inhibitors have made major changes in the management of several cancers with significant improvement in survival. Lung cancer, kidney cancer and Melanomas (a form of skin cancer), have benefitted immensely with the advent of the ICI, so much so that their use is now approved for early cancers, in combination with surgery, chemotherapy or radiotherapy. There is one problem in that having a reliable biomarker to identify who will respond to the ICI therapy is still a work in progress. The higher the PD-L1 expression in the tumour greater the possibility of having a response to ICI.
Additionally, the use of ICI has been approved based on molecular abnormalities rather than the type of cancer. Mutations in genes associated with DNA repair (mismatch repair genes) will result in many mutations arising in the tumour providing an opportunity to trigger an immune response to the abnormal proteins derived from the mutated genes. The mismatch repair pathway genes include MSH2, MLH1, PMS2, MSH6, MSH3, and PMS1. Gene testing for mutations in these genes can be done both at the germline level as well as in the tumour; an additional assay which looks at the functional effect of loss of these gene functions, is Microsatellite Instability (MSI) assay. Tumours with high MSI are more likely to respond to the ICI therapy. The cancers wherein these abnormalities occur include large intestine cancers, uterus cancer, urinary tract cancer (other than kidney), stomach cancer etc.
In addition, tests are available to assess what is known as the Tumour Mutational Burden (TMB), which in a way is the functional effect of the gene mutations not limited to DNA mismatch repair mechanisms. Tumours with high tumour mutational burden will likely benefit from ICI and extends to cancers such as lung cancer.
Challenges with ICI therapy:
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Toxicity: The ICI therapy can lead to a syndrome called cytokine release syndrome which can be life-threatening.
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Immune-related organ damage, including that of the Large intestine, Thyroid, Pituitary, heart, liver, kidney, lung, skin, eyes, etc. Some of these can be life-threatening.
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Financial toxicity: The cost of the therapy will be upwards of Rs 75 lakhs, which most will not be able to afford. Additionally, in some cancers the actual overall survival benefit will be to the tune of few weeks to months. The patient will be better served to always have a second or third opinion when considering ICI therapy for cancers other than lung, kidney, melanomas, and tumours with mismatch repair abnormalities.
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Not all cancers benefit from the use of ICI.
Way Forward
Cancer Immunotherapy is now an essential component of therapy in several common cancers. In some patients, even with advanced disease, they have shown excellent benefit. Unfortunately, this is in a smaller subset. Efforts are underway to identify better biomarkers to identify reliably who would benefit from the ICI, so that unnecessary therapy and financial toxicity can be avoided. It is also essential that the cost of the therapy is brought down to make it affordable to the vast majority of cancer patients in our country.
*This article was first published in the September 2024 issue of BioVoice eMagazine.