Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology.
T-cell receptor (TCR)-based adoptive therapy employs genetically modified lymphocytes that are directed against specific tumor markers. This therapeutic modality requires a structured and integrated process that involves patient screening (e.g., for HLA-A*02:01 and specific tumor targets), leukapheresis, generation of transduced TCR product, lymphodepletion, and infusion of the TCR-based adoptive therapy. In this review, we summarize the current technology and early clinical development of TCR-based therapy in patients with solid tumors. The challenges of TCR-based therapy include those associated with TCR product manufacturing, patient selection, and preparation with lymphodepletion. Overcoming these challenges, and those posed by the immunosuppressive microenvironment, as well as developing next-generation strategies is essential to improving the efficacy and safety of TCR-based therapies. Optimization of technology to generate TCR product, treatment administration, and patient monitoring for adverse events is needed. The implementation of novel TCR strategies will require expansion of the TCR approach to patients with HLA haplotypes beyond HLA-A*02:01 and the discovery of novel tumor markers that are expressed in more patients and tumor types. Ongoing clinical trials will determine the ultimate role of TCR-based therapy in patients with solid tumors.
The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But, despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyper-progression have also been reported. It is therefore essential to understand the molecular mechanisms and identify the drivers of therapeutic response and resistance. In this review, we provide an overview of the current and emerging clinically relevant genomic biomarkers implicated in checkpoint blockade outcome. U.S. Food and Drug Administration–approved molecular biomarkers of immunotherapy response include mismatch repair deficiency/microsatellite instability and tumor mutational burden ≥10 mutations/megabase. Investigational genomic-associated biomarkers for immunotherapy response include alterations of the following genes/associated pathways: chromatin remodeling (ARID1A, PBRM1, SMARCA4, SMARCB1, BAP1), major histocompatibility complex, specific (e.g., ultraviolet, APOBEC) mutational signatures, T-cell receptor repertoire, PDL1, POLE/POLD1, and neo-antigens produced by the mutanome; those potentially associated with resistance include β2-microglobulin, EGFR, Keap1, JAK1/JAK2/interferon-gamma signaling, MDM2, PTEN, STK11, and Wnt/Beta-catenin pathway alterations. Prospective clinical trials are needed to assess the role of a composite of these biomarkers in order to optimize the implementation of precision immunotherapy in patient care.
Purpose: Inhibition of histone deacetylase 6 (HDAC6) is predicted to deliver both direct antitumor activity and modulation of the antitumor immune response. This study describes the development of a novel HDAC6 inhibitor. Patients and Methods: KA2507 was characterized in HDAC biochemical and cellular target engagement assays and in preclinical efficacy models of melanoma and colorectal cancer. In a phase I study, KA2507 was administered orally using a 3+3 dose-escalation design (NCT03008018). Results: KA2507 is a potent and selective inhibitor of HDAC6 (biochemical IC50 = 2.5 nmol/L). Preclinical models demonstrated antitumor efficacy in syngeneic tumor-bearing mice, with translational studies highlighting modulation of the antitumor immune response. Twenty patients were treated in a phase I study. KA2507 was well tolerated; dose-limiting toxicity was not observed up to the maximum dose administered. Pharmacokinetic profiling supported twice-daily oral dosing. Pharmacodynamic analysis demonstrated selective HDAC6 target engagement in peripheral blood cells, free from off-target class I HDAC activity. Stable disease was the best clinical response (7 patients). Three of these patients (adenoid cystic carcinoma, n = 2; rectal adenocarcinoma, n = 1) had prolonged disease stabilization that lasted for 16.4, 12.6, and 9.0 months, respectively. Conclusions: KA2507 is a potent and selective inhibitor of HDAC6 showing antitumor efficacy and immune modulatory effects in preclinical models. In a phase I study, KA2507 showed selective target engagement, no significant toxicities, and prolonged disease stabilization in a subset of patients. Further clinical studies of KA2507 are warranted, as a single agent or, preferably, combined with other immuno-oncology drugs.
Background Data on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with concurrent autoimmune diseases (AID) are limited. Methods We performed a retrospective multicenter review of medical records of patients with cancer and underlying AID who received ICI. The primary endpoint was progression-free survival (PFS). Results Among 123 patients with pre-existing AID who received ICI, the majority had been diagnosed with non-small cell lung cancer (NSCLC, 68.3%) and melanoma (14.6%). Most patients had a rheumatologic (43.9%), or an endocrine disorder (21.1%). Overall, 74 (60.2%) patients experienced an immune-related adverse event (irAE) after ICI initiation, AID flare (25.2%), or new irAE (35%). Frequent irAEs included thyroiditis, dermatitis and colitis. ICI was permanently discontinued due to unacceptable (8.1%) or fatal (0.8%) toxicity. In patients with NSCLC, corticosteroid treatment at the initiation of immunotherapy was associated with poor PFS (HR = 2.78, 95% CI 1.40–5.50, p = 0.003). The occurrence of irAE was associated with increased PFS (HR = 0.48, 95% CI 0.25–0.92, p = 0.026). Both parameters maintained their independent prognostic significance. Conclusions ICI in patients with cancer and pre-existing AID is associated with manageable toxicity that infrequently requires treatment discontinuation. However, since severe AID flare might occur, expected ICI efficacy and toxicity must be balanced. Clinical trial identifier NCT04805099
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