The Power of Prediction
Cancer therapeutics have improved significantly in the past decade and can provide powerful antidotes to deadly disease. However, the desired impact of therapy on cancer is frequently accompanied by side effects, which can range in severity from inconvenient to life threatening.
Identifying biomarkers that predict response to drug or predict adverse reactions to drug are large unmet needs within the cancer field, and was an important area of focus at this year’s American Association for Cancer Research Annual Meeting (AACR), held April 16-20 in New Orleans. Identification of such biomarkers can significantly improve the treatment of patients by reducing exposure to ineffective therapies and by providing clinicians with an early indicator of patient complications, revealing an opportunity to add or change treatment, potentially reducing suffering and allowing patients to receive other treatments that have enhanced efficacy or more acceptable side effect profiles.
Ipilimumab (Yervoy, BMS) is an anti-CTLA 4 antibody that blocks inhibitory signals that downregulate immune responses and is approved by the FDA for use in unresectable or metastatic melanoma. It’s effectiveness in other solid tumors—including NSCLC, SCLC, bladder, and prostate cancer—is currently under investigation in multiple clinical studies. At AACR, Dr. Padmanee Sharma’s lab (MD Anderson) presented data from a recent study investigating the combination of ipilimumab and androgen deprivation therapy in metastatic prostate cancer. Researchers employed Adaptive Biotechnologies immunoSEQ® Assay—which profiles the TCR repertoire by combining multiplex PCR, high throughput sequencing, and bioinformatics—to assess changes in the periphery in response to treatment. They observed that the number of expanded TCR clones within the CD8+ T cell subset in blood was associated with immune related adverse events (irAEs) and correlated with the severity of these events1. The change in repertoire was evident prior to clinical presentation of symptoms, indicating that assessment of the repertoire using the immunoSEQ Assay could give physicians an additional window of time to modify treatment, potentially reducing the severity of adverse events.
These results were underscored at AACR in a study presented by Dr. Larry Fong’s group (UCSF) in which patients with castrate resistant prostate cancer were treated with ipilimumab and GM-CSF, and changes in the TCR repertoire in the periphery also preceded irAEs2. Furthermore, Dr. Antonio Ribas’ group published a study in which metastatic melanoma patients were given another anti-CTLA4 antibody (tremelimumab, MedImmune), and the immunoSEQ Assay was used to demonstrate an increased number of unique TCR clonotypes in the periphery of patients with AEs. This highlights the consistency of the observation that changes in the periphery are associated with adverse events across different anti-CTLA4 therapeutics and malignancies3. Combined, these studies demonstrate the benefit of using the immunoSEQ Assay to assess the TCR repertoire in the periphery of anti-CTLA treated patients and establish a rationale for investigating the use of the immunoSEQ Assay to identify early biomarkers of adverse events.
In addition, the immunoSEQ Assay has already been used to identify predictive biomarkers of response to treatment from tumor infiltrating lymphocytes (TILs)4. Given that most cancer therapeutics impact adaptive immune responses to cancer, the immunoSEQ Assay represents a powerful tool to aid in predicting adverse events and response to therapy, and to positively impact cancer treatment regimens.
 Subudhi, S. et al (2016) AACR Abstract Number 1402
 Oh, D. et al (2016) AACR Abstract Number 4362
 Robert, L. et al (2014) CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire. Clin Cancer Res. 20(9), 2424-2432.
 Tumeh, P. et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568-571.