Advancing Immunotherapy in Oncology

Avishek Roy

Scientific Liaison Manager
4baseCare

Cancer is a disease characterized by uncontrolled growth of cells due to genetic mutations and epigenetic modifications that result in forged expression of genes that regulate cell growth and death. Conventional cancer treatment involves combination of chemotherapy, surgery and radiotherapy which are not optimized as precision treatment. Patients who are unresponsive to conventional treatments have poor prognosis and more probability to cancer reoccurrence.

Precision oncology is an innovative approach which is defined as the development of specifically designed treatments that target the molecular profiling of individual tumors. Each patient’s genetics are used to determine the genes that are mutated to cause cancer. Treatment protocol is created only for them and hence, precision oncology is more effective and having less side effects over conventional treatment.

Immunotherapy and biomarkers
Normally, the immune system identifies and removes malignant cells, however, the cancer cells evade the immune system by creating an immunosuppressive environment. Therefore, recently the focus has been more into immunotherapy which could be able to treat the cancers by restoring the immune system. Immunotherapy is a strategy used to restore and potentiate the patient’s immune system, so that it can recognize, attack, and remove cancer cells. Immunotherapy alone or in combination with conventional cancer therapies can be used to improve treatment outcomes.

Novel immunotherapeutic agents such as chimeric antigen receptor T cell (CAR-T cell) and immune checkpoint inhibitors (ICIs) viz. pembrolizumab, nivolumab, and atezolizumab are used in cancer. Therefore, predictive biomarkers are urgently needed for effective ICI therapy. Programmed cell death ligand 1 (PD-L1), tumor mutation burden (TMB) and microsatellite instability (MSI) are the Predictive biomarkers approved by FDA for ICI therapies. Tumor infiltrating lymphocytes (TILs) are emerging markers, which may prove to be useful predictive markers for ICIs. Data has shown that Immunotherapy can successfully treat the cancers and improved the long term survival of patients in remission cases too. Due to the heterogeneous nature of cancer, patients respond differently to immunotherapy and therefore need to develop technology that has huge data of cancer genomic profile that can help to customize the treatment on individual basis. ICIs are also used with immune-modulators like ipilimumab which is targeting CTLA-4 for the treatment of melanomas. CAR-T cells are genetically engineered to produce an artificial T-cell receptor for use in immunotherapy for the treatment of solid tumors but they are under investigation.

Next Generation Sequencing (NGS)
Immuno-genomics is a relatively new field of cancer research, in which NGS is utilized to obtain genomic profile of both the cancer genome and immune cells DNA. NGS is a high-throughput parallel sequencing technology that has a large amount of genomic information. Comprehensive genomic profiling (CGP) is an NGS approach that uses a single assay to assess hundreds of genes including relevant cancer biomarkers, as established in guidelines and clinical trials, for therapy guidance. Using NGS technology to obtain a cancer genomic profiling for the patient can help customize the treatment to target specific characteristics of cancer and increase the probability of success. NGS databases have the major goal to encourage comprehensive research in the identification and experimental validation of cancer mutations for diagnostic and therapeutic applications. It forms the basis of precision or personalized medicine.

After the completion of the human genome project, the datasets of 33 types of cancer were available publically on TCGA project and International Cancer Genome Consortium (ICGC). The Cistrome Cancer project data combines with chromatin immunoprecipitation (ChIP-seq), and RNA-seq to untangle the mechanism of transcription-regulated gene expression in cancer. MethyCancer database contains high-throughput cancer datasets of DNA methylation and CpG islands, and provides the landscape of epigenetic regulation in cancer. A recent studies have shown potential of publicly available NGS data to make understanding of regulatory mechanisms in cancer.

Precision medicine/ personalized medicine
Precision medicine is the newer term adapted to replace personalized medicine given by U.S National research council (NRC) in 2011. Precision medicine is the development of a patient-specific treatment plan through integration of information from patient’s Electronic health record, genetic and socioeconomic background, and genetic variations in the tumor. Treatment regimens like ICIs which can be tailored for each individual patient in personalized treatment. The advantage of this approach is to improve the patient outcome, reduces adverse events and cost-effective. It is mostly used for the treatment of patients unresponsive to conventional therapy. It covers a wide range of cancer management including cancer screening, monitoring of relapse or recurrence, selection and prediction of effective drugs and personalized immunotherapy.

Steps for the treatment of cancer patients in the era of precision medicine
1. Characterize the genomes of patients’ tumors using recently developed technologies such as next-generation sequencing.
2. Use the genomic data to match therapies for the treatment of cancer.
3. Present an explained list to the treating oncologist that can be used in clinical decision for the treatment of cancer.