Immunotherapy in Cancer Management.. Are we Ready?

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Dr Pierce Chow, Senior Consultant, National Cancer Centre Singapore, Division of Surgical Oncology; President, College of Clinician Scientists Singapore

Cancer is a leading cause of death worldwide. The most recent scientific progress in precision medicine has revolutionized how we improve health and hold the promise of turning cancer into a manageable chronic disease. Co-organized with Singapore’s College of Clinician Scientists, the seminar themed Immunotherapy in cancer management …Are We Ready? took place on Tuesday, September 19, 2017,  in Singapore, where leading clinicians and top-notched researchers from Singapore and Taiwan were convened to fervently discuss and participate in didactic, interactive, and immunotherapy based scientific sharing sessions.

This dinner seminar brought together approximately 70 genomics, molecular pathology and oncology experts from Singapore and Taiwan. The seminar, chaired by Professor Pierce Chow, senior consultant and Co-Director (Surgical) of the Comprehensive Liver Cancer Clinic at the National Cancer Centre Singapore, invited distinguished speakers as below:

(a) Latest Development of immunotherapy by Prof. Salvatore Albani (Duke-NUS)

(b) Application of immunotherapy in clinical oncology by A/Prof Toh Han Chong (National Cancer Centre Singapore)

(c) Diagnostic tools available for immunotherapy by Dr Chen Shu Jen (Chief Scientific Officer, ACT Genomics)

(d) A panel discussion on the promises and challenges of immunotherapy in clinical practice

The emergence and the great potential of NGS herald a new era in genetic diagnostics. Nevertheless, this cutting-edge technology does bring challenges, both at the technical level and in terms of the quality control of the specimens, as well as the interpretation of the results and the curation of the database to be used.

Up-to-date, genomic analysis of tumors has transformed cancer diagnosis and treatment. Patients can ultimately spare their fear of cancer. Doctors, in response, would be thinking out of the box – it’s no longer necessary for them to determine a specific drug for a specific cancer. With the advances in NGS application, cancer can ultimately be made a life-long, manageable disease.

In a conversation with biotechin.asia, Dr Allen Lai, Regional Managing Director of ACT Genomics explains the buzz about immunotherapy and its scope and latest updates in cancer immunotherapy.

Dr. Allen Lai , Regional Managing Director of ACT Genomics Singapore. Credit: ACT Genomics

Can you explain in layman terms, what is this buzz in the industry about immunotherapy and the promise it holds for managing/treatment and cures for diseases such as cancer or infectious diseases

Cancer immunotherapy administers therapeutic agents designed to restore immune response to kill tumor cells. The rationale of using immunotherapy against cancer lies in the fact that cancer is a disease of genetic mutation. Immunotherapy attacks the core of carcinogenesis process – mutation. Cancer immunotherapy has three far-reaching advantages (as well as benefits) that lead to the promise in eradicating cancer: target specificity, memory and adaptability.

Specificity. As one of the foundations of precision medicine, immunotherapy treatment activates T cells and B cells that target specific pathogenic mechanisms in subgroups of cancer patients. As such, immunotherapy holds the promise of being more specific, less toxic and in some instances even of providing the potential for a cure rather than mere therapy over a given pathogenic mechanism.

Memory. Immunological memory is pivotal in cancer immunotherapy and has become the key distinctive hallmark of the immune system. Evidence shows that the human T cell memory system, with great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, has proved to be more capable of controlling malignant tumors. Such long-lasting anti-tumor capacity of memory T cells plays a crucial role in the control of malignant tumors.

Adaptability. Immunotherapy is designed to support immune system adaptability. It’s been crystal clear that cancer cells evolve and mutate over time which results in resistance to conventional anticancer therapies2. The immune system can be finely tuned to address the consequences of immune-incompetence, such as in cancer or infectious diseases, or to control noxious chronic autoimmunity, such as in arthritis.

 

What are some of the diagnostic tools currently available for immunotherapy? 

There are a number of diagnostic tools used to stratify patients suitable for cancer immunotherapy, immune checkpoint inhibitors in particular. Among all, immunostaining of Programmed Cell Death Ligand1 (PD-L1) is one recently FDA-approved biomarker, used by most drug developers. However, PD-L1 staining-based diagnostics have not proved to be a drastic success. As such, other genomic markers such as microsatellite instability (MSI) assay have been approved as the biomarker for two PD-1 inhibitors, e.g., pembrolizumab (developed and marketed by Merck Co.) and nivolumab (developed and marketed by Bristol-Myers Squibb).

Several publications also suggest that tumor mutational burden, either calculated from whole exome sequencing or from comprehensive cancer panel sequencing, can be used to predict a patient’s response to immune checkpoint inhibitor. In addition to protein and genomic markers, studies have been designed to incorporate RNA expression level to reflect tumor microenvironment.

Can you tell us more about NGS technique and how it is revolutionizing precision medicine?

About 300-500 genes among the 20,000 human genes are related to cancer, and cancer is caused by germline or somatic mutations in those cancer-related genes. The conventional molecular diagnostics identify the defect of a single gene by detecting hotspot mutation. However, the development of cancer in most cases may involve more than one gene that leads to overgrowth and proliferation of cancer cells. Using the conventional diagnostics to test multiple genes is not practical as it requires substantial amount of specimen, prolonged turnaround time, and high cost.

The technology of NGS revolutionizes personalized healthcare because this method generates massive sequencing data in a single test run with minimal specimens required. With just a fraction of precious samples, the technique of NGS can achieve an average sequencing depth of 1,000X to detect genetic alterations with high sensitivity. Within a short turnaround time, this method allows a rapid and comprehensive gene analysis that meets the requirements of clinical settings. Through bioinformatics data processing and utilizing clinical databases, gene mutations are matched with the appropriate targeted therapies to provide patients and doctors with personalized treatment options.

An NGS-based sequencing report includes genomic alteration status, the biological function of mutated genes, and shall cover the most relevant clinical evidence. It supports doctors to translate genomic information into a tailored treatment and to make the best therapeutic decision for their patients.

As a biotech company, what is the focus of ACT genomics?

At ACT Genomics, we focus on precision cancer management. We deploy a high throughput state-of-the-art method called next-generation sequencing (NGS) to effectively profile solid tumors retrieved from cancer patients. With our in-house proprietary pipeline in bioinformatics and modified protocols from sample processing to genomics report generation, we can identify most promising matching tailored treatment options, and strategize cancer therapeutics matched for each individual patient along the continuum of cancer care.

We integrate genomic databases with Asian specific genome profiling, deliver medical reports with genetic variants information, therapeutic implications and also provide comprehensive consultation services to empower physicians with evidence based-precise information.

Our flagship NGS assay – ACTOnco™ helps doctors evaluate the patient’s specific tumor mutational burden and predict if the patient is likely to benefit from using immunotherapy with checkpoint inhibitors.

 

What are some of the immunotherapy treatments currently approved and available on the market?

As of October 2017, the FDA approved six immune checkpoint blockades and their therapeutic indication(s), including ipilimumab (CTLA-4 blockade) for melanoma, nivolumab (PD-1 inhibitor) for melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin’s lymphoma, pembrolizumab (PD-1 inhibitor) for melanoma and lung cancer, atezolizumab (PD-L1 inhibitor) for bladder cancer, durvalumab (PD-L1 inhibitor) for locally advanced or metastatic urothelial carcinoma, and avelumab (PD-L1 inhibitor) for Merkel-cell carcinoma.

What are some of the latest developments in immunotherapy in cancer management?

In the last five years, the development of immune checkpoint inhibitor and T cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy which just received FDA approval for relapsed acute lymphoblastic leukemia, have been remarkable for the speed, scale and number of drug approvals. There has been a revival of interest in therapeutic cancer vaccines with the exciting early clinical results of neoantigen vaccines.

Interrogating the tumor microenvironment and searching for biomarkers such as mutation burden will improve cancer immunotherapies. Cutting-edge technology and rational combination clinical trials can potentially improve both processing and clinical efficacy of such therapies.

What is the interest level among the public, currently, to get their genome analyzed for possible genetic defects? Do you think there is a big market for this, already?

For the time being, the concept and praxis of precision oncology are more prevailing among cancer patients and oncologists either to early detect recurrence/resistance or search for treatment options at the advanced stage. As for the general public, the use of genetic testing remains more relevant to individuals at risk of hereditary cancer. In this space, there is a big market to unlock the potential of genetic testing in preventive medicine.

According to the literature, 5%-10% of all cancer cases are hereditary. The most common hereditary cancers are breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer and kidney cancer. Fundamentally, hereditary cancers are caused by mutations in cancer-related genes. Many of those genes help repair damaged DNA, and if these genes do not function correctly, further genetic alterations may develop and cause cancer.

For examples, BRCA1 and BRCA2 genes. Evidence shows mutations in both BRCA1 and BRCA2 increases the risk of developing breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. As such, if one has a family history of cancer types with a high risk of a hereditary cause, he or she may consider cancer genetic testing to find out for inherited mutations in cancer-related genes; once confirmed, it is recommended to start taking actions for cancer prevention and early detection.

 

How far are we, from making, immunotherapy an integral part of the cancer patient’s treatment, when the current paradigm is surgery, radiation, chemotherapy, hormonal therapy and targeted therapy?

Not all patients are likely to benefit from this costly treatment. Patients treated with checkpoint inhibitors respond better to immunotherapy if their tumors harbor high mutational burden.