The fourth day of the ASCO 2021 virtual annual meeting featured clinical trial data of some promising immunotherapy candidates.
Oncolytic Viral Therapy Shows Promising Results in Fighting T-cell Lymphoma
Joselle Cook, MBBS, from the Mayo Clinic presented the results of Phase 1 clinical trial testing the effects of a novel oncolytic virotherapy against hematological malignancies. The therapy consisted of a modified Vesicular Stomatitis Virus (VSV), which was engineered to express two more proteins, interferon beta (IFNβ), and sodium iodine symporter (NIS). IFNβ expression acted as a marker for viral proliferation, and it enhanced host anti-tumor immunity. NIS was used to visualize the viral distribution via SPECT/PET imaging.
For the trial, 15 patients with different hematological malignancies were enrolled. Four different doses were tested to ranging from 5×109 to 1.7×1011 TCID50 (50% tissue culture infectious dose). All doses were tolerated. Interestingly, VSV- IFNβ-NIS therapy at the highest dose resulted in 1 partial response and 1 complete response, both patients suffered from relapsed refractory T-cell lymphoma. The highest dose of VSV- IFNβ -NIS also resulted in stable disease for patients with multiple myeloma.
The efficacy of this therapy will continue to be tested in combination with immune checkpoint inhibitors, and with a larger cohort of T-cell lymphoma patients.
First-in-Class CD11b Modulator Reduces Immunosuppressive Tumor Microenvironment
Dr. Haeseong Park from Washington University, St. Louis presented the results of a Phase 1 clinical trial evaluating the safety and efficacy of GB1275, the first-in-class, oral CD11b modulator. CD11b is expressed in myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), both contribute to an immunosuppressive tumor microenvironment. Pre-clinical studies showed that GB1275 leads to T cell proliferation and polarizes macrophages to an inflammatory state.
The Phase 1 trial tested the safety of GB1275 as a monotherapy and in combination with Keytruda (pembrolizumab), an anti-PD-L1 checkpoint inhibitor. GB1275 was tested at concentrations ranging from 100 mg to 1200mg. Results showed that there was no dose-limiting toxicity, and tumor biopsies showed a reduction in MDSCsand an increase in tumor-infiltrating lymphocytes. Although most patients showed progressive disease, a subpopulation of patients had stable disease. GB1275 at a dose of 800mg plus Keytruda will be evaluated in an ongoing Phase 1 expansion.
Novel Strategies for Overcoming Resistance to Immune Checkpoint Inhibitors
Although checkpoint inhibitors revolutionized cancer treatment, there are still limitations to this therapy. From tumors that develop resistance to tumors that have no immune infiltration, new approaches are needed to enhance this class of treatments.
Dr. Judy Wang from the Florida Cancer Specialists and Sarah Cannon Research Institute presented several therapeutic candidates and approaches to overcome resistance to checkpoint inhibitors. Here we present the highlights:
- SHR-1701 is a novel antibody that targets PD-L1 and TGF-βRII. TGF- β1 can be used by tumors to promote oncogenic processes, and its inhibition could provide therapeutic benefits. In a Phase 1 clinical trial, SHR-1701 was well tolerated, and it had an overall response rate of 17.8%, and activity was durable.
- COM701, a monoclonal antibody against PVRIG, which inhibits T-cell and NK-cell activation, was studied as a monotherapy and in combination with OPDIVO (nivolumab). The results showed that the combination was well tolerated, and it had a disease control rate of 67% including patients with previous resistance to OPDIVO. Currently enrolling for Phase1/2 for combination therapy of COM701+OPDIVO+BMS-986207, an anti-TIGIT antibody).
- Preliminary results of a Phase 2 study evaluating the efficacy of alrizomadlin (APG-115), an MDM2 inhibitor in combination with Keytruda (pembrolizumab). APG-115 has been shown to restore apoptosis and increase CD8 tumor-infiltrating monocyte. The results showed that combination therapy had an overall response rate of 24.1% and a disease control rate of 55.2%.
C-CAR039, a Novel Bi-specific CAR T-Cell Therapy Shines in B-cell Non-Hodgkin Lymphoma Study
Dr. Aibin Liang from the School of Medicine, Tongji Hospital of Tongji University presented topline results for C-CAR039, a bi-specific CAR-T targeting CD19, and CD20. In preclinical studies, C-CAR039 has been shown to eradicate tumors positive for one or both of its targets. The safety and efficacy of C-CAR039 were tested in 25 patients with B-cell non-Hodgkin lymphoma.
Results showed the C-CAR039 was well tolerated, with the most common side effects being cytokine release syndrome, neutropenia, anemia, and thrombocytopenia. Crucially, the overall response rate for all patients was almost 93% with a complete response of 85.3%. The median time to complete response was 1 month.
At 6 months, the progression-free survival was 83.2%. Interestingly, the proliferation of modified T cells correlated with B cell depletion, providing a possible mechanism of action. The expansion trial and dosing are ongoing.