Immunotherapy for cancer has been studied in the laboratory and in early-phase trials for decades. Larger trials were not often successful enough, though in the last five years, a revolution has centered around the clinical success of checkpoint blockade with CTLA-4 and PD-1 antibodies.
Abstract
Immunotherapy for cancer has been studied in the laboratory and in early-phase trials for decades. Larger trials were not often successful enough to lead to incorporation of immune-based approaches into standard of care. In the last five years, a revolution has occurred, centered around the clinical success of checkpoint blockade with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) antibodies. These and other newly licensed biologic drugs are promoting potent and durable clinical responses in patients including those with tumors not historically considered “immunogenic.” However, there are still toxicities associated with immunotherapies, and the majority of treated patients do not have durable responses; hence, there is a critical need for standardized and validated biomarkers that yield actionable insights into immunotherapy efficacy.
Introduction
Biomarkers for cancer immunotherapy have been sought for decades. The use of Interleukin-2 (IL-2) for melanoma and renal cancer can lead to durable complete responses, but in a small minority of patients and with considerable toxicity.1Interferon-alpha for melanoma in the adjuvant setting can reduce the frequency of recurrence, but the effect is not very large, there are significant toxicities, and the regimen is a year long.2A test to identify patients who benefit from these approaches, a predictive biomarker, would be valuable to avoid ineffective therapies and toxicities for patients.
Biomarker Types
With the recent clinical successes of cancer immunotherapy comes the increasingly urgent need to identify patients who can benefit from immunotherapy interventions. The optimal biomarker would be a simple blood test that would accurately identify patients who could benefit from available therapies. Other types of biomarkers that would be of utility are assays that would indicate soon after treatment whether or not a patient was benefiting from a therapy in time to change treatment plans. They would also provide a measure of a treatment’s mechanism of action, which would yield important information to understand and optimize approaches and rationally define combinations. For small-molecule signal transduction pathway inhibitors such as vemurafenib, the assay is simple: does the tumor express a mutated BRAF gene, yes or no? For biologics that modulate the immune system, the biomarker question is more complex.
Prognostic Biomarkers
While there are many candidate biomarkers of interest, most are prognostic biomarkers that suggest a subset of patients who are more likely to have a better outcome after the initiation of treatment. Candidate prognostic biomarkers include inducible T-cell co-stimulator (ICOS) upregulation on T cells and reduced CD8+ T cell to regulatory T cells (Treg) ratio in a tumor infiltrate after CTLA-4 blockade3-5, PD-L1 expression on tumors before PD-1 blockade treatment6, myeloid-derived suppressor cell (MDSC) frequency7, CD3/CD8/CD45RO memory T cell infiltrate into tumors (the “Immunoscore”)8-10, tumor mutation burden11,12, and others. These biomarkers are measured in blood and tumor samples and are undergoing further testing, standardization, and validation.
To summarize the state of the field, identify hurdles, and make recommendations to move the field of immunotherapy biomarkers forward, the Society for Immunotherapy of Cancer (SITC)13-17 reconvened the Biomarkers Task Force Steering Committee18to create four working groups to address four key areas in biomarkers science and assay development. Each group is led by leaders in the area and consists of experienced members of academia, industry, and government. Each working group is completing a white paper to appear in theJournal for ImmunoTherapy of Cancer (JITC).19The topics are: 1) assay standardization and validation (Magdalena Thurin, PhD, and Giuseppe Masucci, MD, PhD); 2) novel biomarker technologies (Jianda Yuan, MD, PhD); 3) immune regulation and high-throughput approaches (David F. Stroncek, MD); and 4) tumor microenvironment and baseline measures (Sacha Gnjatic, PhD). In addition to a summary meeting on April 1, 2016, at NCI with a meeting report to follow inJITC, the Task Force has published a series of biomarker technology primers to concisely describe promising technology approaches to biomarker identification.20-26
While the field of cancer immunotherapy has had a great number of FDA approvals for antibody checkpoint molecule blockade therapeutics for melanoma, lung cancer, and other tumors (with more expected) as well as approved virus therapeutics27-29, future breakthroughs in validated biomarker development will be a critical next step.
References
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