Biomarkers that may have value in the context of PD-1 checkpoint immunotherapy strategies, checkpoint targets on macrophages, and advances in cellular immunotherapies dominated conversations during the second day of the 2019 annual meeting of the American Society of Clinical Oncology (ASCO19) in Chicago.
Jeffrey S. Weber, M.D., Ph.D., of the New York University Langone Medical Center, kicked off the day by discussing how inflammation-associated interleukin-6 (IL-6) and C-reactive protein (CRP) are connected to clinical outcomes in patients with inoperable stage 3 or 4 melanoma. This work, which was led by F. Stephen Hodi, M.D., of the Dana-Farber Cancer Institute and Harvard Medical School, involved looking at three trials: the Phase 2 CheckMate-064 (NCT01783938), in which patients were treated with dual PD-1 (nivolumab) and CTLA-4 (ipilimumab) checkpoint immunotherapy; the Phase 3 CheckMate-066 (NCT01721772), in which patients were treated with PD-1 immunotherapy plus chemotherapy (dacarbazine); and the Phase 3 CheckMate-067 (NCT01844505), in which patients were treated with combined PD-1 and CTLA-4 immunotherapy.
Jeffrey S. Weber, M.D., Ph.D., discusses IL-6 and CRP in clinical outcomes for melanoma patients at ASCO19.
Overall, Weber, Hodi, and CRI Scientific Advisory Council clinical director Jedd D. Wolchok, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, who was also involved in the work, found that higher levels of IL-6 and/or CRP were associated with poorer overall survival in all the treatment groups. Furthermore, when either T cells or dendritic cells were exposed to CRP before they interacted with one another, it significantly inhibited the activation of T cells and prevented them from forming proper immunological synapses, which is necessary for T-cell activation and killing. This led Weber to suggest that these biomarkers may have prognostic value and that targeting these molecular pathways in combination with checkpoint immunotherapy could potentially improve patient responses and survival rates.
Other potential biomarkers were explored by Ines Esteves Domingues Pires Da Silva, M.D., of the Melanoma Institute Australia, in work that was led by CRI Clinical Team Leader Georgina V. Long, M.D., Ph.D., and involved CRI Clinical Team Leader Richard A. Scolyer, M.D., also of the Melanoma Institute Australia. The team performed comprehensive molecular profiling of patients with metastatic melanoma—looking at factors related to the tumor cells themselves, the tumor microenvironment, the peripheral blood, and other patient characteristics—in order to predict responses to either PD-1 immunotherapy alone or in combination with CTLA-4 immunotherapy. In particular, they identified two factors—high numbers of tumor mutations and high expression of an interferon gamma-related gene signature—that were associated with significantly higher response rates. In patients with both these characteristics, 100% responded to treatment, and in patients with one of these characteristics, 67% responded. In patients with neither of these characteristics, only 34% responded, highlighting the importance of both immune recognition and activation in successful patient outcomes.
Ines Esteves Domingues Pires Da Silva, M.D., discusses biomarkers in checkpoint immunotherapy treatment at ASCO19.
David B. Page, M.D., of the Earle A. Chiles Research Institute at the Robert W. Franz Cancer Center, spoke about two studies. The first, which involved Hodi, looked at a Phase 1 trial (NCT03013218) targeting the CD47 checkpoint that cancer cells can use to protect themselves against being “eaten” (phagocytosed) by macrophages. When ALX148, which blocks CD47, was used in combination with a HER2-targeting antibody (trastuzumab), it produced responses in 22% of the 18 patients with metastatic cancer of the stomach or gastro-esophageal junction who were treated. Combined CD47 and PD-1 (pembrolizumab) immunotherapy also led to responses in 16% of the 19 patients with metastatic head and neck cancer, including 30% of those who had not previously been treated with PD-1 immunotherapy. Importantly, targeting CD47 increased the infiltration of macrophages into patients’ tumors.
David B. Page, M.D., discusses two studies at ASCO19.
The second study, which involved Wolchok and Weber, looked at how CTLA-4 checkpoint immunotherapy might be able to prevent recurrence when given after surgery in patients with high-risk, stage 3 melanoma that was completely resected in a Phase 3 trial (NCT00636168). This adjuvant (post-surgical) immunotherapy led to a 25% reduction in risk of recurrence and a 27% reduction in risk of death in these patients.
The benefits of using PD-1 immunotherapy (pembrolizumab) after surgery in patients with stage 3 melanoma was highlighted by Kurt A. Schalper, M.D., Ph.D., of the Yale School of Medicine. In the Phase 3 KEYNOTE-054 (NCT02362594), which involved Long, Schalper showed that PD-1 immunotherapy was associated with a 44% reduction in the risk of recurrence. Interestingly, patients who had low-grade immune-related adverse events (irAEs) were more likely to benefit from immunotherapy, supporting the biological link between side effects and the anti-tumor activity of PD-1 immunotherapies. Unfortunately, these benefits were not observed in patients who had grade 3-4 irAEs and had to receive immunosuppressive steroids.
Kurt A. Schalper, M.D., Ph.D., discusses checkpoint immunotherapy post-surgery at ASCO19.
Geraldine Helen O’Sullivan Coyne, M.D., Ph.D., of the National Cancer Institute, discussed a Phase 1 trial (NCT03406871) in which patients with advanced stomach or colorectal cancer were treated with PD-1 immunotherapy (nivolumab) plus the targeted therapy regorafenib. In this work, which involved CRI scientist Hiroyoshi Nishikawa, M.D., Ph.D., of the Japan National Cancer Center, of the 50 patients treated, 44% of the stomach cancer patients and 36% of the colorectal cancer patients responded—and 48% of patients had their disease stabilize. They also found that the levels of regulatory T cells (which can dampen anti-cancer immune responses) decreased in patients who responded to the combination.
Geraldine Helen O’Sullivan Coyne, M.D., Ph.D., discusses a Phase 1 trial for stomach and colorectal cancer at ASCO19.
Katharine A. Price, M.D., of the Mayo Clinic, provided an update on the Phase 2 trial (NCT02760498) that led to the approval of cemiplimab, a PD-1 immunotherapy, in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). In this work, which was led by CRI Clinical Team Leader Scott J. Antonia, M.D., Ph.D., formerly of the Moffitt Cancer Center and now at the Duke Cancer Institute, 43% of patients with locally advanced CSCC responded to treatment, and 36% had their disease stabilize. Meanwhile, in patients with metastatic CSCC, 47% responded and 15% had their disease stabilize. Impressively, patients treated with this immunotherapy did not see their cancers worsen until a median of 18.4 months, compared to historical values of 5.5 months for chemotherapy-treated patients and 4.1 months for patients treated with the EGFR-targeting antibody cetuximab.
Katharine A. Price, M.D., provides an update on a skin cancer clinical trial at ASCO19.
Finally, Day 2 of ASCO19 also featured several talks that focused on cellular immunotherapies for patients with advanced cancer.
CRI CLIP Investigator Ignacio Melero, M.D., Ph.D., of Clínica Universidad de Navarra, discussed a study involving Weber as well as CRI Scientific Advisory Council member and CRI Clinical Team Leader John M. Kirkwood, M.D., of the University of Pittsburgh Medical Center. The study was a Phase 2 trial (NCT02360579) in which patients with stage 3-4 unresectable melanoma who had previously been treated with PD-1 immunotherapy were then treated with a cryopreserved (frozen) tumor-infiltrating T cell product called Lifileucel. Overall, among these 55 heavily pre-treated patients, there were 21 responders (38%), with 21 experiencing disease stabilization.
Ignacio Melero, M.D., Ph.D., discusses a Phase 2 trial for melanoma at ASCO19.
A second study discussed involved Michel Sadelain, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, who serves as a member of the CRI Clinical Accelerator Leadership. In this Phase 1 trial (NCT01044069), patients who eventually received CAR T cells were first treated with a bridging chemotherapy regimen with the goal of keeping their disease in check long enough to create and infuse the CAR T cells for their treatment.
Of the 53 patients who received CAR T cells, 19 received a high-intensity bridging regimen and 34 received low-dose. Notably, the higher intensity regimen was associated with more high-grade complications relating to infections due to its immunosuppressive effects but did not result in higher rates of success. As Melero noted, most patients with advanced, heavily pre-treated acute lymphoblastic leukemia won’t respond to chemotherapy, therefore the low-dose bridging should suffice—and may even be preferable—prior to CAR T cell immunotherapy.
Lastly, a poster presented by Amir A. Jazaeri, M.D., of the University of Texas MD Anderson Cancer Center, highlighted the benefits of another tumor-infiltrating T cell therapy—LN-145—in patents with recurrent, metastatic, or persistent cervical cancer. Of 27 patients, 44% responded and an additional 44% saw disease stabilization.
That’s it for Day 2 of ASCO19! Look for more exciting immunotherapy news from ASCO in the days ahead by following our blog and remember to join our “Cancer Immunotherapy Insights from ASCO” Twitter chat (#CIMchat) on June 11, at 12pm ET, moderated by Sharon Begley, senior science writer at STAT.
Photos by Arthur Brodksy, Ph.D. for Cancer Research Institute