When most people think of the city of Atlanta (Georgia, USA), they think about Coca Cola, the Olympic stadium, or perhaps the Delta Airlines hub. But last week (29 March - 3 April 2019), this southern city was home to more than 22,500 attendees for the AACR annual meeting. For one week, Atlanta was flooded with top-quality science and ambitious visions that will shape the future of cancer therapies.
The field of oncology is entering an era of maturity, evidenced by this year’s focus not only on precision medicine but also on developing new tools to understand and utilize the existing therapies better based on clinical results. This “forward and reverse” translational research and “empirical to rational” study design cycle1 was pervasive across all sessions. We saw that the biomarkers, predictive algorithms, single-cell analysis technologies, and organoids were in the spotlight as methodologies to help such rational designs. (image source: Gibbs et al, CPT 2018)
Let AI decide
Go/no go decision making in cancer drug development has never been this difficult, thanks to the increasing number of novel therapeutics with many potential combination regimens. In each step of development – from pre-clinical (target selection, disease models) to clinical (defining the patient population, competition, combinations) – the art of decision-making is pivotal to reduce research costs, drug prizes and setbacks. A presentation by David Feltquate from Bristol-Myers Squibb (BMS) showed employing predictive algorithms based on empirical parameters obtained from phase I / phase II trials has predicted past IO successes and failures. Such algorithms weigh components of safety, pharmacodynamics and clinical effects to pinpoint key measures that inform decision making.
Dance of biomarkers
If you are working in an early-stage drug development program and approaching the clinic, be prepared to be asked (many times) “Do you have a biomarker?” Probably amongst the most popular words of AACR 2019, biomarkers are now considered as key to rational, precision-medicine therapies and successful clinical results. Beyond typical mutated genes(BRCA1/2)and overexpressed proteins (HER2, PD-L1), Tumor Mutational Burden (TMB), Minimal residual disease (MRD), Microsatellite Instability (MSI) and their spatio-temporal variations were deliberately discussed. Some take-home messages include: not every biomarker works for every tissue, and changes apply through duration of the disease and treatment. There is no universal biomarker yet, however, novel approaches such as methylscape (epigenome assays), protein phosphorylation and highly sensitive analysis on circulating tumor cells are exciting possibilities that are awaiting validation. Biomarkers take a central spot in patient stratification, predicting and overcoming resistance and recurrence.
Tumor heterogeneity: single-cell technologies
Do all cancer cells do the same thing within the tumor? The answer is no. Tumor heterogeneity and variation in gene expression is a long-standing debate but now superior single-cell technologies are discovering how tumor cells are different. 3D Imaging Mass Cytometry developed in Bodenmiller lab (University of Zurich) combines mass cytometry with ‘omics techniques to systematically describe cell phenotypes and their heterogeneity in tumors. Bernd showed that breast tumor tissue ecosystems can be clustered in 17 single-cell pathology groups2. Arjun Raj from UPenn presented another key technique coined as molecular Time Machine, a method connects single cell fate with gene programs. Arjun et al used time machine to follow resistant melanoma colonies that were formed after treatment with vemurafenib and identified biomarkers resulted in resistance. (Image source: Arjun Raj lab)
CAR-T and synthetic lethality: tip of the iceberg?
Understanding drug resistance is a priority now, as four PARP inhibitors are approved and more programs targeting DNA Damage Response (DDR) and synthetic lethality are in clinical development. Mark O’Çonnor (AstraZeneca) presented the data for combinations of inhibitors targeting ATR, Wee1 and PARP. Such combination therapies disrupted rewired homologous recombination and fork protection pathways in resistant BRCA-deficient cancer cells.
There is a great effort to enhance CAR-T treatment efficacy and reduce toxicity in the clinic. Currently, 364 CAR-T trials are listed in clinicatrial.gov and numbers are growing. Dr. Saad Kenderian from Mayo Clinic showed that CD19 therapy relapses are due to loss of CAR-T cells as well as an upregulation of inhibitory role of checkpoint blockade. Modulating T cell phenotype and combination therapy with checkpoint inhibitor treatment (pembroluzimab) will be the future direction to overcome relapses. Meanwhile, more and more solid tumor targeting CAR-Ts and allogeneic cell therapies are being translated into the clinic. Phase I data from Baylor College of Medicine showed complete response for two out of ten sarcoma patients with HER2+ expression. Three saw their cancers kept in-check, and five saw no benefit. Dr. Ewelina Morawa from CRISPR therapeutics presented future directions for anti-CD33 and anti-CD70 allogeneic CRISPR/Cas9 edited CAR-Ts targeting AML and multiple solid tumors retrospectively in preclinical models. Overall, these cell therapies and DDR targeting programs are likely to expand as our molecular understanding deepens.
Highlighted clinical results
Although AACR mainly focuses on early research and preclinical work as opposed to immediate clinical applications, several remarkable clinical studies were presented. In pancreatic cancer, the PRINCE trial testing a combination of nab-paclitaxel, nivolumab, and APX005M, (Apexigen’s anti-CD40 mAb) showed exciting early results: 54 percent of the 24 evaluable patients responded. Clovis oncology presented interim data from phase II study in first-line maintenance setting in pancreatic cancer patients with rucaparib, suggesting disease control with no new safety signals in 19 evaluable platinum-sensitive patients with BRCA1, BRCA2, or PALB2 mutations after 9.1 months of treatment. In lung cancer, a pooled analysis from four studies of nivolumab showed that 14% of NSCLC patients who received treatment (after failing other treatments) are still amongst us after four years. The typical five-year life expectancy for these patients was 10%. In other tumors, Amgen presented a pilot neoadjuvant TNBC trial with TVEC (oncolytic virus product, talimogene laherparepvec) and paclitaxel. This showed promising results, with 5 out of 9 patients showing complete pathologic response. In hematological malignancies: final results of the phase III ADMIRAL trial with gilterinib (FLT3 kinase inhibitor) was presented. Gilterinib improved survival for patients with relapsed or refractory acute myeloid leukemia (AML) harboring a FLT3 mutation compared with standard chemotherapy regimens. The ADMIRAL study has practice-changing implications for treatment of relapsed/refractory AML. Patients now can be tested for FLT3 mutations and benefit from this approach.
On the horizon
Patricia M. LoRusso closed the conference by highlighting the developments in immunotherapy as a metaphor to Gartner's Hype cycle3 for technological innovations. After three years in a row of growing focus on IO research with inflated expectations, the paradigm shift is on the horizon for enlightenment and clinical productivity. Future research emphasis will be on defining resistance and especially distinguishing between intrinsic and acquired resistance. There is a need for understanding clinical and molecular definitions and improving methods. On the technology side, digitizing clinical trial assessments, digitizing cancer and patients through evidence-based prediction algorithms are already being implemented, as Peter Kuhn and Jorge J. Nieva (University of Southern California) discussed in a back-to-back session. (Image source: Anderson Cancer Center)
1-Gibbs et al, CPT, February 2018 Bedside to Bench: Integrating Quantitative Clinical Pharmacology and Reverse Translation to Optimize Drug Development
2-Wagner J et al, Cell Accepted.