Cancer, a formidable adversary in the realm of human health, perseveres as a prominent contributor to global mortality. Through a persistent evolution over recent decades, the multifaceted domain of cancer research has fervently propelled the advancement of novel therapeutic interventions. Among these, the burgeoning prominence of immunotherapy has emerged as a pivotal cornerstone alongside the established pillars of surgical intervention, chemotherapeutic approaches, radiation therapy, and precision-targeted therapies. An article titled 'Nature Milestones in Cancer' was jointly published by Nature Genetics and Nature Medicine. It summarizes 14 significant milestone events in cancer research during the 21st century, showcasing unraveling the intricacies of cancer pathogenesis and the concomitant evolution of transformative treatment modalities.
8. Immune Checkpoint Inhibitors
The application of the immune system in cancer therapy dates back over a century. The immune system serves as a crucial guardian through its surveillance function. Nonetheless, cancer cells have evolved diverse strategies to elude immune surveillance and counterattacks. In a pivotal development in 1996, James Allison and his research team demonstrated the efficacy of antagonistic antibodies targeting CTLA-4 in inducing tumor rejection responses in mice. This discovery unveiled the therapeutic potential of immune checkpoint inhibitors (ICIs).
In 2003, Allison and his collaborators conducted the inaugural human study employing the CTLA-4 antibody, ipilimumab. This study not only provided clinical validation of the treatment concept but also marked the identification of the immune checkpoint ligand PD-L1 and its receptor PD-1. This discovery spurred the development of novel ICIs.
The year 2010 saw the initiation of the first human trial with the PD-1 antibody, nivolumab, which showcased sustained regression in various tumor types. In 2014, the FDA granted approval for the first PD-1 inhibitor, pembrolizumab, for the treatment of ipilimumab-refractory melanoma. Subsequently, in 2015, PD-1 inhibitors gained gradual approval for the treatment of other tumor types. In 2016, the FDA greenlit the first PD-L1 inhibitor, atezolizumab. Presently, ICIs have become integral in the treatment of a minimum of 17 advanced malignant tumor types.
9. Transforming T Cells to Kill Cancer Cells
T cells, pivotal agents within the immune system, possess the remarkable ability to identify and eliminate infected and cancerous cells when they detect them. Adoptive cell therapy (ACT) leverages this potent cytotoxic capability of T cells to combat tumors. In the 1980s, a groundbreaking milestone was achieved in cancer treatment as Steven Rosenberg isolated tumor-infiltrating lymphocytes (TILs) from melanoma patients, activated and expanded them, and reintroduced them into the patients' systems. This pioneering research unveiled the potential for modified T cells to persist for extended periods, a pivotal requirement for the success of ACT.
In 1989, Zelig Eshhar introduced a transformative concept by fusing the variable region of antibodies with the constant region of T cell receptors (TCRs), giving rise to chimeric antigen receptors (CARs). This innovation granted T cells antibody-like specificity. Subsequent advancements came in 2002 when Michel Sadelain and colleagues enhanced CAR design by consolidating the intracellular domains of TCR and the crucial co-stimulatory receptor CD28 into a single molecule. This refinement contributed to sustaining T cell expansion, functionality, and longevity.
In 2010, James Kochenderfer and collaborators achieved a significant breakthrough by demonstrating the effectiveness of CAR-T cell therapy within patients' bodies. In 2017, CD19 CAR T cell therapy received FDA approval for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) and adults with aggressive lymphomas.
10. Epigenetic Drivers of Tumor Initiation and Progression
The genetics and biology of pediatric cancers differ from those in adults. Epigenetic mutations in histone proteins, known as "oncohistones", have been identified as fundamental drivers of many aggressive pediatric cancers. In 2012, groundbreaking research revealed a high frequency of somatic mutations in pediatric high-grade gliomas, primarily affecting the H3 histone genes. Oncohistones disrupt transcriptional regulation by altering chromatin remodeling and accessibility, promoting tumor initiation and progression. In 2013, multiple studies identified EZH2 as a therapeutic target and confirmed that the loss of H3K27me3 is associated with upregulation of genes involved in neural development. A 2017 report suggested that certain loci, like CDKN2A, retain H3K27me3, leading to selective gene silencing programs that facilitate tumor initiation while preserving the identity of tumor cell origins. In 2019, research indicated that oncohistones are not limited to gliomas and sarcomas, as somatic variants of core histones were found in different tumor types. However, it remains unclear whether these variants are driver mutations or passenger mutations, and the downstream mechanisms are not yet well understood. Currently, some histone deacetylase inhibitors and tyrosine kinase inhibitors are undergoing clinical trials, and therapeutic interventions based on genetic profiling of tumors in clinical trials are likely to increase the chances of success.
11. Tumor Cell Clonal Diversity Forms the Basis for Cancer Progression
Before the advent of second-generation sequencing technologies, an unprecedented level of resolution was achieved in characterizing the cancer genome, offering the promise of guiding cancer treatment based on genotype. In 1976, Peter Nowell proposed that cancer is an evolutionary process, and subsequently, James Goldie and Andrew Coldman suggested that tumor genetic heterogeneity increases treatment resistance. In the 2000s, several studies demonstrated the complexity of clonal evolution and supported the notion that clonal diversity is fundamental to disease progression and treatment resistance. In 2011, Anderson and Notta, among others, tracked the evolutionary pathways of different subclones during the progression of acute lymphoblastic leukemia. They found that the level of genetic heterogeneity within the leukemia-initiating cell subpopulation was similar to the genetic heterogeneity within the leukemia cell population in the samples. The branching evolutionary trajectories did not conform to a linear model of cancer evolution. In 2012, Gerlinger et al. confirmed that cancer is a highly dynamic entity, prompting a shift in thinking from linear cancer evolution to branched cancer evolution. They also highlighted the extreme heterogeneity of cancer genomes. Genetic heterogeneity exacerbates treatment resistance, making a comprehensive understanding of cancer evolution dynamics and assessing tumor heterogeneity crucial for prediction, drug development, and treatment.
12. Targeting "undruggable" non-kinase proteins.
In the early 21st century, dozens of kinase inhibitors were advancing toward clinical use, while research progress in oncology regarding crucial non-kinase targets remained relatively scarce. The RAS gene is one of the most widely mutated oncogenes, and since its discovery in 1982, no drug has successfully been developed to target RAS, earning it the label of an "undruggable" target. In 2013, a breakthrough unveiled by Shokat shed light on the possibility of employing small molecules to form a covalent bond with the KRAS-G12C mutant, a prevalent RAS mutation found in non-small cell lung cancer. This groundbreaking revelation sparked immense enthusiasm within the scientific community, eventually leading to the development of two notable drugs, namely AMG510 and MRTX849. These drugs exhibited promising effectiveness in their initial forays into clinical trials, marking a significant stride in the ongoing battle against this form of cancer. However, not all RAS mutations are G12C, and compounds targeting other KRAS subtypes are also in development, often found in NSCLC, pancreatic cancer, and colorectal cancer.
13. The Impact of Gut Microbiota on Antitumor Immune Responses
Currently, the efficacy of numerous cancer treatments hinges upon the activation of antitumor immune responses. Nevertheless, a critical question arises regarding the potential impact of the gut microbiota on the host's reaction to cancer therapy, particularly through its influence on the immune system. In the year 2013, the scientific communities led by Laurence Zitvogel and Giorgio Trin Chieri catapulted forward with two revolutionary studies, underscoring the pivotal role played by a diverse array of gut microbiota in instigating both innate and adaptive immune responses to a spectrum of three distinct cancer treatments. Notably, findings from the research conducted by Iida et al. highlighted that mice afflicted with tumors and lacking essential gut microbiota exhibited compromised responses when subjected to CpG oligodeoxynucleotide (ODN), oxaliplatin chemotherapy, and interleukin-10 receptor (IL-10R) blockade.
In 2015, two additional studies further identified different bacterial species that regulate antitumor immune responses under treatment pressure, such as Bifidobacterium spp. and B. fragilis. In 2018, a significant scientific breakthrough was achieved through the collaborative efforts of Zitvogel, Gajeski, and Jennifer Wargo. Their collective research unveiled three independent studies, shedding light on the pivotal role played by gut commensal bacteria in dictating the success of anti-PD-1 immune checkpoint inhibitors (ICIs) within the context of melanoma and epithelial tumor patients. Remarkably, it was discovered that the intricate makeup of the gut microbiota might serve as a determining factor contributing to primary resistance against ICIs.
14. The Potential of Artificial Intelligence in Cancer Diagnosis and Monitoring
Leveraging the potential of artificial intelligence (AI) in healthcare can not only facilitate the automation of diagnostic procedures but also streamline the operations for healthcare professionals involved in patient care. Over the past decade, the volume of digital clinical data, encompassing electronic health records, genomics, and digital biomedical images, has experienced an unprecedented surge.
A pivotal moment arrived in 2017 when Esteva et al. unveiled a groundbreaking study that employed computer vision in the realm of cancer detection. By harnessing a substantial repository of digital images capturing various skin conditions, they successfully trained and validated deep convolutional neural networks, enabling precise differentiation between benign and malignant lesions.
Bejnordi et al. achieved a milestone in the accurate identification of lymph node metastasis in breast cancer through the utilization of deep-learning models. In another significant stride, Hollon et al.'s prospective clinical trial demonstrated the efficacy of AI-driven systems in delivering precise diagnoses for patients undergoing brain cancer surgery.
These groundbreaking advancements represent only the initial strides in the realm of integrating big data and artificial intelligence in the field of oncology. This integration holds the promise of a unique interface, and experts are anticipating monumental breakthroughs within this research domain over the course of the next 10 years.
References
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- Kochenderfer J. N.; et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood, The Journal of the American Society of Hematology. 2010, 116(20):4099-102.
- Wu G.; et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012, 44(3):251-3.
- Gerlinger M.; et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New England Journal of Medicine. 2012, 366(10):883-92.
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