Margaret Foti, PhD, MD, chief executive officer of the American Association for Cancer Research (AACR), kicked off this year’s opening ceremony celebrating an outstanding year for the organization. This includes the launch of its 10th working group dedicated to pathology in cancer research and importantly the achievements made against cancer, with an overall meeting theme of “Inspiring Science, Fueling Progress, Revolutionizing Care” to reflect the full gamut of cancer research. The annual meeting was held in San Diego, California and attracted a record number of more than 23,000 registrants. The packed 5-day program encompassed a staggering 7,200 plus abstracts and more than 800 oral presentations showcasing improved outcomes, novel biomarker development and drug design together with cutting edge innovations that are truly transforming the pace of research in cancer biology. Given the breadth of topics that I covered over my five days at the AACR and the scope of work presented, I’m splitting my overview into two parts, with this first recap herein focused on drug targets and my second, focused on updates with spatial biology. Enjoy!
It is increasingly clear that accumulated genomic instability of cells resulting from deficient DNA damage/repair (DDR) responses are strongly associated with the development and progression of cancer. Interestingly though, such defects can also be exploited from a therapeutic perspective and an expanding repertoire of DDR-targeting agents and inhibitors including the success of PARP inhibitors in cancers with homologous recombination repair (HRR) defects (HRDs) now include, ATM, ATR, CHK1, WEE1, and DNA-PK, some of which are already undergoing clinical trials. It was great to see one of my mentors from my academic post-doctoral days, Michael Kastan, MD, PhD, FAACR, now a professor at Duke University and executive director of Duke Cancer Institute, demonstrate the potential of an investigational inhibitor of the DNA repair proteins ATM and DNA-PK to sensitize cells to radiation during the plenary session. Together with colleagues he identified XRD-0394, a novel dual inhibitor of ATM and DNA-PK, that could be delivered systemically. Based on highlighted preclinical data, they also initiated a phase I clinical trial to evaluate the safety and pharmacokinetics. The novel drug demonstrated limiting toxicities and importantly patient tumor samples indicated that the drug successfully inhibited ATM in patients. Future work will look into combining XRD-0394 with various other therapies, such as immune checkpoint inhibitors, PARP inhibitors, and cytotoxic drugs. Modulation of DDR pathways in cancer therapy was featured in many of the numerous poster sessions throughout the meeting as well as additional oral presentations. This includes promising new data from the Ivy Brain Tumor Center at the Barrow Neurological Institute who in collaboration with AstraZeneca are conducting a Phase 0/1b clinical trial to evaluate the ATM inhibitor, AZD1390 in patients with recurrent WHO grade IV glioma (https://aacrjournals.org/cancerres/article/84/7_Supplement/CT044/742338/Abstract-CT044-A-phase-0-1b-study-of-AZD1390-plus). Certainly, the 2024 meeting underscored our understanding of DNA damage and repair biology and showcased novel DDR-targeting molecules exploiting replication stress through DDR inhibition as an emerging anti-cancer therapy.
Without doubt potential cancer treatment has evolved and changed with a better understanding of the molecular mechanisms underlying cancer, including inherent heterogeneity, development of treatment resistance, and the intricate web of cellular pathways that contribute to its malignancy. At AACR 2023 much focus was on novel antibody strategies with the rise of Antibody-Drug Conjugates (ADCs) and T-cell engagers, as well as improvements in Chimeric Antigen Receptor (CAR)-T design. This year also saw some promising early phase trials in those areas as well as the rise of PROTACs.
ADCs combine the potent payload cytotoxicity of chemotherapy with an antigen-specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types. With several TROP-2 directed ADCs now currently in development, as well as over 60 posters highlighting its use in various tumor types, it’s clear that along with other top targets HER2, Tissue factor (TF), Nectin-4, FRα, and EGFR there was a lot of excitement around ADCs in solid tumors. Specifically, a TROP2-directed ADC developed by Merck and Kelun-Biotech for utility in gastric cancer associated with poor prognosis produced promising disease control and potentially extended survival in pretreated patients with gastric or gastroesophageal junction cancer (https://aacrjournals.org/cancerres/article/84/7_Supplement/CT038/742426/Abstract-CT038-Preliminary-efficacy-and-safety). Treatment with the novel ADC led to a 22% objective response rate in 41 evaluated patients, nine of whom had a partial response. And the 12-month OS rate was 32.6%. Jordi Rodon, the study’s lead author and associate professor of investigational cancer therapeutics at MD Anderson Cancer Center, noted that “by using a different linker-payload combination, we did not see the interstitial lung diseases associated with other ADCs,”
Without doubt, CAR-T therapy has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory B cell malignancies with CD19 and BCMA recognized as the most common targets. Poseida Therapeutics’ lead CAR-T program highlighted new data from a subset of patients in an ongoing Phase 1 study of its lead program, P-BCMA-ALLO1. (https://aacrjournals.org/cancerres/article/84/7_Supplement/CT071/742485/Abstract-CT071-Clinical-activity-of-P-BCMA-ALLO1-a). Results showed that three of the five (60%) patients with relapsed/refractory multiple myeloma who had progressed following BCMA-targeted therapy achieved clinical responses with P-BCMA-ALLO1, a novel investigational B-cell maturation antigen (BCMA)-targeted allogeneic, T stem cell memory (TSCM)-rich chimeric antigen receptor T-cell (CAR-T) therapy manufactured from healthy donor T-cells and available off-the-shelf. The findings provide additional evidence that the therapy “could be an appropriate treatment for a broader range of patients with multiple myeloma, including those with relapsed/refractory disease whose cancer progressed following prior BCMA-targeted therapy,” Syed Rizvi, M.D., chief medical officer at Poseida.
Despite persistent challenges with the complexity of the tumor microenvironment, tumor heterogeneity, and on-target off-tumor toxicity, there was also hopeful news for efficacy of CAR-T therapy in solid tumors. Samer Srour from MD Anderson presented long-term follow-up data from a Phase I dose-escalation study of CTX130TM, a CD70-targeting allogeneic CAR T cell therapy for patients with clear cell renal cell carcinoma (ccRCC), after prior treatments with at least one checkpoint inhibitor and a tyrosine kinase inhibitor (https://aacrjournals.org/cancerres/article/84/7_Supplement/CT002/742428/Abstract-CT002-CTX130-allogeneic-CRISPR-Cas9). Of note, cytokine release syndrome was observed in only 50% of patients, and all events were grade 1 or 2. Only 19% of patients experienced grade 3 infections. CTX130 exhibited encouraging anti-tumor activity and a strong safety profile, and the durable CR of over three years is the first and longest observed with allogeneic CAR T cell therapy in refractory solid tumors. These results support further studies investigating CD70-targeting CAR T cell therapy for ccRCC and other CD70-expressing solid tumors. The data also highlighted the importance of building CAR T products that will be persistent and of high apheresis quality, which itself has been the subject of recent guidelines from the FDA, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-development-chimeric-antigen-receptor-car-t-cell-products
With over 60 abstracts submitted, the hot new buzzword at this year’s meeting was PROteolysis-TArgeting Chimeras, affectionally called PROTACs. This novel precision medicine strategy targets key proteins for proteolytic degradation to ultimately induce cancer cell killing using the ubiquitin proteasome system to selectively add polyubiquitin chains onto a specific protein target to induce proteolytic degradation. Indeed, earlier this year, Paul Workman in an AACR opinion piece noted that “the success of targeted protein degraders lies in their transient binding to targets (which allows them to have catalytic activity and continually degrade their targets) and their ability to tolerate low binding affinities (which makes them more suitable than conventional reversibly acting inhibitor drugs)”. PROTACs are at the crossroads of many cancer research areas with a particular focus on targeting historically undruggable proteins. One such target is the transcription factor SOX2, who’s overexpression is associated with poor survival of cancer patients due to SOX2 promoting proliferation, survival, invasion/metastasis, cancer stemness, and drug resistance. To date, little progress has been made in the efforts to discover SOX2 inhibitors, largely due to undruggable nature of SOX2. There was a flurry of interest therefore when EPD Biotherapeutics highlighted the development of EPDegTM, a next-generation engineered protein degrader platform, in order to overcome the limitations of small molecule-based PROTAC. They reported a series of SOX2-targeting bioPROTACs, being composed of a nanobody against SOX2 with high affinity and several ubiquitin E3 ligases with deletion of the natural substrate binding domain to instead allow highly selective degradation of SOX2 protein. (https://aacrjournals.org/cancerres/article/84/6_Supplement/3256/740884/Abstract-3256-Novel-SOX2-targeting-bioPROTACs-for). While there are still some associated challenges with PROTACs, such as achieving optimal tissue specific delivery, pharmacokinetics, pharmacodynamics and improved off-target side effects and toxicities, I’m confident that by AACR 2025 we’ll see much more data with this promising application.
This year, with nine poster presentations and an exhibitor spotlight theatre, we at NeoGenomics had a very productive and busy meeting. Presentations included research in key areas, including addressing the tumor microenvironment using end to end spatial biology strategies, next-generation sequencing and comprehensive multi-omics approaches in identifying genetic alterations in cancerous cells, and much more. Through collaborations with leading institutions and a dedicated R&D and Pharma Services operations team, our company continues to contribute to the broader landscape of oncology research, emphasizing the connection and importance of collective efforts in advancing cancer care. “Our presence at the AACR 2024 Annual Meeting reflects our dedication and investment in advancing the field of precision oncology through groundbreaking research and collaborative partnerships," noted Chris Smith, CEO of NeoGenomics. For more information on all our AACR 2024 abstracts and poster presentations, please visit neogenomics.com/newsroom/literature.
AACR 2024 showcased that improvements in many of the technologies, particularly in overall design and choice of target, appeared to have made some newer iterations of the drugs safer and more effective which is especially true for CAR-T and ADCs. The exciting integration of these developments into the clinic is poised to deliver the much-needed promise to patients of better treatment outcomes and overall care. I hope everyone had a great and inspiring conference and again if you missed any of our posters and talks please feel free to click on the links provided and visit our website for more information.