Noted This Week

This week: Special content from the AACR Annual Meeting 2021 and other news

April 9–15

NCI Director Norman "Ned" Sharpless told attendees of the American Association for Cancer Research (AACR) Annual Meeting 2021 that progress must speed up dramatically. To cut the cancer mortality rate in half from its peak in the early 1990s, "will require a considerable acceleration of what we’ve been able to achieve in the last few decades," he said. At the current rate of 2.2% per year, it would take until 2040 to reach that goal—"that’s too long… Using all of our many tools of prevention and screening and new therapies, I think we can get there by 2026—that’s 5 years from now. This would require an average reduction in cancer mortality of about 4% per year, which is considerably faster than the rate of decline we’ve ever done before."

In a high-level outline of its budget priorities for fiscal year 2022 released on April 9, the Biden Administration proposed a total increase of $9 billion for the NIH. Of that, $2.5 billion would be distributed to the NIH’s various institutes, of which the NCI is the largest, Sharpless reported. If approved by Congress, "that would translate into a substantial increase in the NCI’s budget for FY2022. This would be key to allowing the NCI to continue to increase paylines and success rates for grant applications."

Aiming to cure major diseases, including cancer and diabetes, the Biden Administration proposed creating a $6.5 billion medical research agency that would be "housed" within the NIH. The Advanced Research Projects Authority for Health would be modeled after the Defense Advanced Research Projects Agency, wherein funding decisions are made by program managers rather than peer reviewers, and projects receive milestone-driven payments instead of multiyear grants.

During the AACR meeting, Melissa Davis, PhD, of Weill Cornell Medical College in New York, NY, discussed how a lack of genomic data from diverse populations can lead to disparities in cancer research. "Just about any population that is of non-European descent has a higher rate of reporting back on a mutation panel a variant of unknown significance," she said. These panels are used to determine eligibility for trials, she added, so "if their mutations are undefined and therefore by definition unknown and unactionable, this a systematic exclusion of these individuals for their access to trials."

The director of the Cold Spring Harbor Laboratory Cancer Center in New York, David Tuveson, MD, PhD, was inaugurated as president of the AACR on April 12, succeeding Antoni Ribas, MD, PhD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center. Lisa Coussens, PhD, of the Knight Cancer Institute at Oregon Health & Science University in Portland, will become the organization’s president following Tuveson’s 1-year term.

At the AACR meeting, Eric Klein, MD, of Ohio’s Cleveland Clinic reported data from a prospective study on Galleri, GRAIL’s multicancer early detection test. Researchers assessed Galleri, which relies on sequencing of methylation regions in circulating cell-free DNA to detect malignancies, on 2,823 patients with cancer and 1,254 healthy people. The assay had a specificity of 99.5% and a sensitivity of 51.5% across cancer types and stages; sensitivity increased with cancer stage. Among patients who tested positive for cancer, Galleri accurately determined the tissue of origin in 88.7% of cases. "These data support the foundation for population-scale clinical implementation of this test," Klein concluded.

Engineered natural killer (NK) cells can target specific antigens via expression of chimeric antigen receptors (CAR). As an alternative approach to endow NK cells with CAR-like activity, Katayoun Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, reported the generation of cord blood–derived NK cells precomplexed prior to infusion with AFM13 (Affimed), a bispecific innate cell engager that binds CD16 on NK cells and CD30 on tumor cells. Preliminary results from a phase I trial indicate that adoptive transfer of AFM13-complexed CAR-like NK cells shows antitumor activity with minimal toxicity in patients with relapsed/refractory CD30+ Hodgkin lymphoma.

Tumor heterogeneity can make it difficult to determine which tumors are immunologically "hot" and thus more likely to respond to immunotherapy. Elisabeth De Vries, MD, PhD, and colleagues at the University Medical Center Groningen in the Netherlands explored whole-body PET imaging and reported that tumor uptake of radiolabeled PD-1 antibodies is associated with prolonged progression-free and overall survival. "Whole body information about what’s happening at the tumor and normal tissue level might provide insights into what’s happening during the complex processes induced by immunotherapy," she told AACR meeting attendees.

Also at the AACR meeting, Ross Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, outlined studies demonstrating the power of single-cell sequencing technology to precisely identify the timing of mutations and define clonal trajectories. Follow-up studies have shown that clonal genotypes are associated with distinct immunophenotypes, he said, and advances in in vivo modeling and multi-omics single-cell sequencing will provide insight into the mechanisms underlying evolutionary mutational trajectories and enable elucidation of the biological underpinnings of clonal hematopoiesis.

Michel Sadelain, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, described several advances in chimeric antigen receptor (CAR) T-cell therapy that might improve its efficacy—modulation of transcriptional regulation, signaling calibration, and epigenetic enhancement. He also introduced a novel CAR design called HIT receptor and demonstrated its greater antigen sensitivity compared with "traditional" CAR T-cell therapy.

The 4-1BB (CD137)/HER2 bispecific cinrebafusp alfa (PRS-343; Pieris) may be active in patients with HER2-expressing cancers who have previously received multiple therapies. In a phase I trial presented at the AACR meeting, five of 42 evaluable patients responded to the therapy, and 17 more patients experienced stable disease; two of the responses—including one complete response—were in eight patients treated at the highest dose level. The agent increased CD8+ T cells, NK cells, and cytotoxic activity in the tumor microenvironment.

Researchers described the discovery of INCB89550, a PD1/PD-L1 inhibitor at the AACR meeting that is being tested in clinical trials. Using high-throughput screening, the team initially identified a compound that exhibited dose-dependent inhibition of PD-1–PD-L1 interactions. Analysis of the amino acid residues critical for drug activity revealed that the inhibitor blocked binding by interacting with PD-L1 directly at the PD-1–PD-L1 binding interface—a rare occurrence because this interface is largely flat and lacks a defined binding pocket. The researchers then used rational, structure-guided design of improved inhibitors derived from the initial hit to identify INCB086550 as a candidate for clinical development.

Also at the AACR meeting, researchers reported promising preclinical results for the targeted thorium conjugate HER2-TTC (BAY2701439; Bayer). The agent consists of a radioactive thorium isotope bound by a chelator that is covalently linked to a HER2 antibody. It kills HER2-expressing cells and neighboring cells by delivering alpha radiation that induces DNA damage—for which there is no known resistance mechanism. Preclinical results suggest that HER2-TTC may have anti-tumor activity in cancers with low levels of HER2 expression, as well as those that are resistant to other HER2-targeted agents. The agent is now being tested in a phase I trial of HER2-expressing malignancies.

In other news:

The FDA authorized the marketing of the artificial intelligence device GI Genius (Cosmo Artificial Intelligence), which assists clinicians in detecting lesions during a colonoscopy. In a prospective trial of patients with adenoma or carcinoma, the technology identified lesions in 55.1% of cases, compared with a 42% detection rate for colonoscopy alone. The device, which uses a machine learning algorithm, attaches to an endoscope and identifies regions of interest in the colon, alerting clinicians to take a closer look.

The agency also granted accelerated approval to sacituzumab govitecan (Trodelvy; Immunomedics), an antibody–drug conjugate, for patients with locally advanced or metastatic urothelial cancer who have received chemotherapy and a PD1/PD-L1 inhibitor. The approval was based on the phase II TROPHY trial, in which patients had an objective response rate of 27.7% and a median duration of response of 7.2 months.

GlaxoSmithKline (GSK) halted the phase II INDUCE-3 trial testing feladilimab, an inducible T-cell co-stimulatory agonist, plus pembrolizumab (Keytruda; Merck) in head and neck cancer based on the recommendation of an independent data monitoring committee. The company will also discontinue the phase II INDUCE-4 trial assessing feladilimab plus pembrolizumab and chemotherapy in head and neck cancer. GSK did not share details of the committee’s recommendation.


TROP2 ADC Intrigues in NSCLC
February 17
Datopotamab deruxtecan elicited responses in almost a quarter of patients with relapsed/refractory disease in trial.

Research Watch