Editorial: Twenty Years On from Sequencing the Human Genome, Personalized/Precision Oncology Prepares to Meet the Challenges of Checkpoint Inhibitor Therapy

Twenty years ago, on April 14, 2003, the International Human Genome Project was declared complete, with the identification, mapping, and sequencing of approximately 92% of the human genome [1]. International efforts and collaborations have resulted in sequencing cancer genomes to identify significant genetic alterations in most human cancers [2,3]. Studies have identified two main areas for therapeutic targeting of human cancer [2,3]. First, cancer genome annotation methods have identified mutated, amplified, or deleted cancer genes [2,3]. Also, context-specific genes essential for cancer cell survival and proliferation or survival are being identified in cell lines and tumor tissue [2,3].

The terms personalized medicine and precision medicine can and are used interchangeably in oncology. The National Cancer Institute defines both personalized medicine and precision medicine as: “a form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease,… and uses specific information about a person’s tumor to help diagnose, plan treatment, or prognosis” [4,5].

In 2017, Schwartzberg and colleagues reviewed the rapid developments in precision oncology, which is the molecular profiling of tumors to identify targetable alterations [6]. At the time of the publication of the update from these authors, precision oncology had entered mainstream clinical practice [6]. However, there have been many challenges in implementing precision oncology in real-world clinical practice. Genomic testing involves coordination between patients, clinical laboratories, and clinicians to deliver high-quality tissue samples that can be analyzed by appropriate next-generation sequencing (NGS) molecular analysis before treatment selection can begin [6]. A further challenge has been the development of resistance to targeted therapies, which may alter as cancer progresses [6].

During the past two decades, drug discovery and development in oncology have been driven by targeted therapy to molecular and protein biomarkers expressed by individual tumors [6,7]. Non-small cell lung cancer (NSCLC) has been the paradigm for a truly personalized approach to targeted therapy for malignancy [6,7]. For NSCLC and other types of cancer, as molecular techniques evolve and become more cost-effective, patient and tumor tissue testing continue to provide more specificity for treatment targets to improve outcomes for more patients diagnosed with cancer [6].

In the past decade, the role of immune checkpoint inhibitors has received increasing attention. Early clinical trials resulted in regulatory approvals for immune therapies in patients with advanced NSCLC [8]. T-cell responses to antigens, including tumor-associated antigens, are mediated by the interaction between stimulatory and inhibitory signaling molecules, known as immune checkpoints [9,10]. Targets of inhibitory checkpoints include programmed death 1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) [9,11].

In 1995, Krummel and Allison described the immunomodulatory effects of CTLA-4 on T-cell responses [12]. In 2000, Freeman and colleagues described the immunoinhibitory effects of the PD-1 receptor [13]. Most clinical studies on personalized therapy in oncology now involve immune checkpoint inhibitors [14]. Most immune checkpoint inhibitors are therapeutic antibodies that activate T-cell-mediated antitumor responses [14]. In the past decade, global regulatory agencies have granted marketing approval for more than 80 applications for more than ten checkpoint inhibitors that oncologists currently use [14].

Immune checkpoint inhibitors have been a significant advance for patients with cancer. They are not only used for palliative care for patients with melanoma or lung cancer but are now used with or without chemotherapy [14]. Immune checkpoint inhibitors extend survival in patients with NSCLC, melanoma, colorectal cancer (CRC), and Hodgkin’s lymphoma. [14]. Recently, immune checkpoint inhibitors have been extended as adjuvant therapy for patients with resected melanoma or lung cancer [14]. In 2022, Cercek and colleagues reported the findings from a prospective phase 2 study that included 12 patients with mismatch repair-deficient stage II or III rectal adenocarcinoma (NCT04165772) [15]. The single-agent anti-PD-1 monoclonal antibody, dostarlimab, resulted in a complete response (CR) in all 12 patients (100% response; 95% CI, 74–100) [15]. In this study, patients were followed-up for 12 months after completion of dostarlimab therapy, and further long-term studies are required to assess the duration of response [15].

Therefore, increasing investment in preclinical studies, clinical development, and clinical trials by the pharmaceutical industry of immune checkpoint inhibitors is justified. Up to December 2021, more than 5,500 ongoing studies actively recruited patients for clinical trials on immune checkpoint inhibitors worldwide [14]. Also, in 2021, the total revenue associated with immune checkpoint inhibitor prescribing approached $60 billion, with pembrolizumab alone generating approximately $20 billion in sales [14]. Therefore, the pharmaceutical industry has an economic incentive to identify and invest in new indications for immune checkpoint inhibitors. However, recent concerns have been raised regarding the redundancy of many ongoing clinical trials with similar trial designs and statistical assumptions [16]. Also, the high cost of immune therapies for cancer can result in inequities between those with access to health care and those without access [16]. A further limitation of the use of immune checkpoint inhibitors is that most responses in patients with metastatic cancer are only partial and are incomplete, with the possible exception of reported cases of long-term remission in patients with NSLC and melanoma [16]. Also, of the many indications for using immune checkpoint inhibitors in treating solid tumors, the beneficial effect in patients with hematologic malignancies other than Hodgkin’s lymphoma remain limited [16]. It is important to note that immune checkpoint inhibitors may result in severe toxicities in some patients, resulting in adverse skin, lung, and liver events, with some patients developing autoimmune conditions [17]. A reported 1% fatality rate is associated with treatment with immune checkpoint inhibitors [17].

Adverse events (AEs) associated with immune or immunotherapy are referred to as immune-related AEs (irAEs), which are graded in severity according to the Common Terminology Criteria for Adverse Events (CTCAE), which also assists in comparing toxicities across clinical trials. In 2019, a systematic review conducted by Arnaud-Coffin and colleagues identified that the rate of irAEs in patients treated with anti-PD-(L)1 was 74%, with 14% of patients experiencing severe or grade ≥3 irAEs [18]. The rate of irAEs in patients treated with anti-CTLA-4 inhibitors was 89%, with 34% of patients experiencing severe or grade ≥3 irAEs [18]. Even more concerning was that for patients treated with a combination of immune checkpoint inhibitors, the rate of irAEs was 90%, with 55% of patients experiencing severe or grade ≥3 irAEs [18]. The presentation of the most common irAEs, including dermatitis, enteritis, and thyroiditis, differed from standard chemotherapy-related AEs [18]. The timing of irAEs is much less predictable, and some severe irAEs may persist long after treatment has ceased [18].

There have been several clinical guidelines for the identification and management of irAEs, from the European Society for Medical Oncology (ESMO), the American Society for Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN). In 2021, the Society for Immunotherapy of Cancer (SITC) updated its clinical practice guideline on immune checkpoint inhibitor-related AEs [19]. The SITC panel included recommendations for diagnosing, grading and managing single and combination irAEs associated with immune checkpoint inhibitors [19]. These latest SITC clinical practice guidelines include evidence-based and consensus-based recommendations for medical professionals to guide and improve clinical decision-making and patient outcomes at a time when immune checkpoint inhibitors are the standard of care in treating several cancers [19].

There is also an urgent need to refine treatment approaches that increase the overall T-cell response and include normal and mutant tumor antigens rather than a specific target. For example, Krishna and colleagues recently identified tumor-specific mutant peptide antigens in several solid tumors [20]. Krishna and colleagues have detected and expanded ex vivo antigen-specific and tumor-infiltrating T-cells, which have been used as immune therapy in some patients with solid tumors and with promising results [20]. The way forward for improved use of immune checkpoint inhibitors in oncology requires methods to define tumor-specific epitopes that will generate a cytotoxic T-cell response in patients to provide a truly personalized form of immune cancer therapy [21]. Also, antibodies have been developed in preclinical and clinical studies that activate specific T-cell Vβ antigen components of the T-cell antigen receptor that identify 30 different subsets of T-cells [21]. An antibody to a specific Vβ epitope activates and expands only the individual T-cell subset, resulting in a strong antitumor response with reduced toxicity in murine tumors resistant to checkpoint inhibitors. Clinical trials of the effects of Vβ-activating human T-cell antibodies are currently underway.

Also, the Vβ target in T-cell lymphoma and leukemia with clonal Vβ identity has been recently reported by Li and colleagues, who developed a CAR T-cell against the T-cell receptor Vβ T-cell receptor in mouse models [21]. The findings from this preclinical study may be important because of the persistent unmet need for treatment of T-cell malignancy [22]. Other potential developments in immune therapy in oncology, driven by molecular biology and precision medicine, include using natural killer (NK)-cell therapy modified to express an anti-CD19 CAR, or CAR-NK cells, or bispecific antibodies that target the T-cell receptor β chain [23]. Also, because CTLA4 and PD-1 are not the only immune inhibitory pathways, it may be possible to use immune checkpoint inhibitors in combination with inhibitors of other T-cell immune suppressor pathways [23].

Conclusions

Twenty years on from sequencing the human genome, preclinical and clinical studies have supported personalized/precision oncology. Checkpoint inhibitors are now integrated into standard-of-care for patients with several types of cancer. The remaining challenges include developing antigen-specific and less toxic T-cell-based immune therapy. However, there is hope that new molecular-based technologies could overcome the current challenges of treatment of cancer patients with immune checkpoint inhibitors.