The Society for Immunotherapy of Cancer’s 34th Annual Meeting hosted an array of multidisciplinary and interactive sessions focused on basic and applied cancer immunotherapy.
The introduction of Immune Checkpoint Inhibitors (ICIs) has caused a revolution in cancer therapy; these treatments reactivate the immune system and lead to a potent anti-tumor response. The discovery of new checkpoint targets is a perpetual goal for immuno-oncology researchers worldwide. At SITC 2019, an entire session was dedicated to these novel emerging targets in cancer immunotherapy.
Emerging Targets in Cancer Immunotherapy
In the session titled “Immune Checkpoints: Newer Targets and an Update on Combinations” scientists like Dr. Don Gibbons, M.D., Ph.D. (University of Texas MD Anderson Cancer Center) and Ahmad A. Tarhini M.D., Ph.D. (Moffitt Comprehensive Cancer Center and Research Institute) were among those who presented their work on new viable targets for immunotherapy.
Dr. Gibbons discussed “Targeting CD38 to optimize PD-(L)1 and CTLA-4 immune checkpoint blockade” in a preclinical model of non-small-cell lung cancer (NSCLC). In pharmacologic and genetic models of anti-PD-(L)1 resistance, CD38 altered the tumor metabolic microenvironment and influenced multiple immune cell types. A combination of anti-PD-L1 and anti-CD38 improved therapeutic response. Moreover, anti-CD38 prevented and reversed the adaptive resistance to PD-1/CTLA-4 blockade in multiple in vivo models. Upregulation of CD38 was associated with resistance in multiple cell types, including Ly6C+ monocytes, and Ly6C blockade reversed tumor resistance. In the ICON Project (Immunogenomic profiling of NSCLC Project), Dr. Gibbons’ team mapped tumor subsets from patients by correlating T Cell profiles with tumor RNA signatures. CD38 levels correlated with a T Cell inflamed signature score, T Cell infiltration, and suppression of CD8+ T Cell proliferation in this cohort. In the phase II NEOSTAR study, nivolumab and nivolumab plus ipilimumab increased proliferative and activated tumor infiltrating lymphocytes (TILs). Thus, a parallel analysis of preclinical models and patient samples will best guide understanding of the immune landscape, development of clinical biomarkers, and testing for treatment strategies.
Dr. Tarhini presented “The emerging role of TLR agonists in cancer immunotherapy”. The immune system has evolved highly conserved pattern recognition receptors, such as the toll-like receptor 9 (TLR9) family, through which immune cells detect unmethylated CpG DNA as a “danger signal” and induce a Th1 response. A TLR9 agonist encapsulated in noninfectious virus-like particles (VLPs), CMP-001, induced type 1 IFN and stimulated the innate immune system. This induction of type I IFN was dependent on anti-Qβ, unmethylated CpG DNA, and plasmacytoid dendritic cells (pDCs). Currently, a phase 1b study of intratumoral CMP-001 plus pembrolizumab in resistant melanoma as well as a phase II trial of neoadjuvant nivolumab plus intratumoral CMP-001 in high risk resectable melanoma are ongoing. Another molecule of interest is SD-101, a synthetic CpG-ODN agonist of TLR9 that stimulates pDCs to release IFN-α, TNF, IL-12 and mature into efficient antigen-presenting cells (APCs), leading to enhanced innate and adaptive immune responses. Localized SD-101 delivery optimized the generation of tumor-reactive cytotoxic T Cells through dendritic cell (DC) activation. The combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-(L)1 therapy is currently being assessed in a phase 1b/2 study. This combination treatment activated the immune system in immunologically cold tumors. Another TLR9 agonist, tilsotolimod, with ipilimumab in second line treatment may also have potential in the clinic.
The Dark Side of Immunotherapies
Unfortunately, ICIs are also associated with a wide spectrum of adverse side effects affecting multiple organs including the skin, gastrointestinal tract, endocrine system, liver, lung, nervous system, and musculoskeletal system. It is no surprise that scientists at SITC shared a wealth of information and new discoveries in their effort to overcome these sometimes-deadly immunotherapy-related adverse events (irAEs).
Jarushka Naidoo, M.B.B.Ch. (Johns Hopkins University) was a co-chair of the session on “Current IO Immunotherapy” and presented “Clinical considerations of irAEs”. In a comprehensive introduction, she outlined key milestones for cancer immunotherapy and irAEs, followed by CAR-T cell therapy-specific cytokine syndromes and neurotoxicity. Dr. Naidoo described the diagnostic workup, management, mechanisms, and pathobiology of immune-related toxicities such as colitis, skin disorders, hypophysitis, pneumonitis, thyroiditis, rheumatologic irAEs, and myocarditis brought on by specific treatments, e.g., CTLA-4 inhibition, PD-1/PD-L1 inhibition, and combination therapies. Dr. Naidoo stressed the importance of organizing an immune-related toxicity team consisting of multiple specialties to work with CAR-T cell-treated patients as well as to achieve clinical, translational, and educational goals. Her team’s prospective study for irAEs (i.e., steroid-refractory pneumonitis) is ongoing.
Virginia Pascual, M.D. (Weill Cornell Medical College) discussed autoimmunity and lessons from immune profiling in her talk entitled “Old and emergent players in human autoimmunity”. irAEs are mainly “organ-specific” rather than “systemic” and are more common with CTLA-4 blockade than with PD-1 blockade. These adverse events tend to improve with treatment interruption. Dr. Pascual described immune profiling for IFN-based immune signatures in patients with systemic lupus erythematosus (SLE) as an example of how this type of signature can be used perhaps to monitor irAEs. IFN has a complex and context-dependent role in cancer immunotherapy. Longitudinal monitoring of pediatric SLE patients revealed molecular heterogeneity in signatures including that for IFN response, neutrophils, and plasmablasts. In these cases, SLE pathogenicity was self-amplified through autoantibodies and endosomal nucleic acids sensed by pDCs. The identification of a neutrophil signature has elucidated human neutrophil biology and allowed for the discovery of novel adaptive immune pathways in SLE. In addition, neutrophils associated with lupus release interferogenic DNA and increased the mitochondrial retention of oxidized mtDNA. Interestingly, a distinct CXCR5-CXCR3+PD-1+CD4+ T helper cell subset shared features of oxidized mtDNA CD4+ T cells expanded in SLE blood. Dr. Pascual concluded her talk by expanding on the role of CD4+ T cells in autoimmune disorders, including rheumatoid arthritis.
Michael L. Dougan, M.D, Ph.D. (Massachusetts General Hospital, MGH) focused on “Gastrointestinal (GI) toxicities of checkpoint blockade”. The gut is the most immunologically complex barrier; therefore, the disruption of immune homeostasis leads to a broad spectrum of GI toxicities. With immunotherapy, the type of toxicity is dependent on the targeted pathway. Dr. Dougan described symptoms and diagnosis of enterocolitis, the most common GI toxicity from anti-CTLA-4, PD-1, and PD-L1 antibodies as well as the use of endoscopy to determine the severity and extent of inflammation. To manage immune toxicities and improve cancer immunotherapy, Dr. Dougan mentioned that steroids should be administered cautiously. Data taken at MGH suggests that steroids inhibit the antitumor response in metastatic melanoma patients treated with ipilimumab. Microscopic colitis brought on by checkpoint blockade can be treated with concurrent budesonide. Dr. Dougan concluded by discussing the mechanism behind checkpoint-mediated colitis. CTLA-4 and PD-1/PD-L1 cause distinct phenotypes of colitis, implicating different regulatory roles in the gut. TNF-α is a key regulator to drive checkpoint-mediated colitis as anti-TNFα, infliximab, is highly effective. Interestingly, TNFα blockade overcomes resistance to anti-PD-1 therapy in a mouse melanoma model.
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