Blogs

Targeting the telomeres of non-small cell lung cancer cells to overcome resistance to immune checkpoint inhibitors

1492. Telomere-targeting agent THIO in sequence with cemiplimab demonstrates long-term therapeutic benefits beyond treatment cessation - A phase 2 THIO-101 trial in advanced ICI resistant NSCLC patients.

Victor Zaporojan (MAIA Biotechnology, Inc., Chicago, IL, USA) presented an ongoing phase 2 study investigating 6-thio-2’-deoxyguanosine (6-thio-dG; THIO), a first-in-class small molecule targeting telomerase positive (TERT+) cancer cells, in combination with cemiplimab for patients with advanced non-small cell lung cancer (NSCLC) resistant to immune checkpoint inhibitors (ICI). THIO is recognized by telomerase and is incorporated into telomeres in cancer cells. The presence of THIO in telomeres causes telomere instability, resulting in uncapping of chromatin ends and cancer cell death. Approximately 80% of cancers and 78% to 83% of all cases of NSCLC are TERT+, thus THIO represents a potential new treatment option for the treatment of ICI-resistant NSCLC. Prior studies indicate that THIO followed by ICI exhibits potent and durable anti-tumor activity in animal models of cancer. The study enrolled 89 patients with progressive NSCLC who had previously failed one or more prior line of ICI, and 84% of patients had undergone two or more prior lines of therapy. The study used a modified 3+3 design, and the safety lead-in (Part A) of the study enrolled 10 patients who received 360 mg THIO followed by cemiplimab. In the dose-finding portion of the study (Part B), 79 patients were assigned to groups that received 360 mg, 180 mg, or 60 mg THIO followed by cemiplimab. 79 patients received one or more doses of THIO. The combination of THIO and cemiplimab was well-tolerated, and most treatment-related adverse events were Grades 1 or 2. Among the 69 evaluable patients who had completed at least one post-baseline assessment, partial responses (PRs) were reported for 9 patients and 7 PRs were confirmed by a second scan. 19 patients survived beyond 12 months, and treatment is ongoing for 18 patients. One of the patients has received 25 cycles of therapy, suggesting a potential for long-term treatment benefit. Among patients receiving 180 mg THIO in the third-line (3L) setting (n=8), median progression free survival was 24.1 weeks, and the 6-month overall survival rate was 75%. The overall response rate was 38%, compared to 6 to 10% with chemotherapy in other studies. In patients receiving all dose levels of THIO in 3L setting (n=20), the disease control rate was 85%, higher than what has been observed in previous studies with chemotherapy (25% to 35%), and the median survival follow-up time is currently 11.5 months. THIO exhibited an on-target effect: paired samples from patients with stable disease or a partial response showed a significant increased telomere dysfunction-induced foci-positive circulating tumor cells from Day1 to Day 5 of treatment cycle 1 (paired T-test <0.05), which was not observed in patients with progressive disease. These data indicate THIO in combination with cemiplimab exhibits durable activity in a hard-to-treat patient population, and its safety profile suggests it has potential to be administered for longer periods, potentially translating to longer survival.

Intratumoral treatment of solid tumors with an Fc-engineered CD40 agonist

615. Intratumoral Fc-engineered agonistic CD40 antibody induces tumor rejection and systemic antitumor immunity in metastatic cancer patients. A bench-to-bedside and back approach

Juan Osorio (Memorial Sloan Kettering Cancer Center and The Rockefeller University, New York, NY, USA) presented a phase 1 dose escalation study of 2141-V11, an Fc-engineered anti-CD40 agonist antibody with enhanced binding to the inhibitor FC-gamma receptor IIB (FcγRIIB). Previous studies have indicated that CD40 agonists promote effective T cell responses in preclinical models, but have limited clinical efficacy in humans, partly due to increased significant toxicities in humans. Engagement of FcγRIIB is critical for antitumor activity of CD40 agonistic antibodies, and 2141-V11 has exhibited enhanced dendritic cell activation and T cell responses in a variety of tumor models. The study consisted of 12 patients with metastatic solid tumors and metastatic lesions in the skin that could be treated by intratumoral injection. Patients were heavily pre-treated and exhibited a prior poor response to conventional immunotherapy. Intratumoral injection with 2141-V11 was safe. No dose-limiting toxicities were observed, and most treatment-related adverse events were mild (Grade 1 or 2). 6 of 10 evaluable patients experienced tumor shrinkage, with a disease control rate of 40% and an overall response rate of 20%. Complete responses (CRs) occurred in two patients, one with melanoma and one with hormone positive breast carcinoma. CRs were long-lasting with a median duration of response of 12 months. Increased leukocyte infiltration and tertiary lymphoid structure (TLS) formation at lesions correlated with CR, and TLS were not observed in non-responding patients. Tumor regression, long-term immune memory, and tertiary lymphoid structures were observed in injected and in non-injected lesions in a lateral orthotopic humanized mouse model of breast cancer. 2141-V11 is safe and exhibits long-lasting anti-tumor activity in a subset of patients, and the study has been expanded to investigate 2141-V11 in tumor-specific scenarios. Phase 1 studies of intratumoral/intravesical administration of 2141-V11 for bladder cancer, prostate cancer, and recurrent or newly diagnosed malignant glioma are ongoing.

Remodeling the tumor immune microenvironment of glioblastoma

991. ST101, an inhibitor of the transcription factor C/EBPß, promotes an immune-active tumor microenvironment in a window of opportunity (WoO) study of patients with glioblastoma (GBM)

Jim Rotolo (Sapience Therapeutics, Inc., Harrison, NY, USA) presented ST101-101, a surgical window of opportunity (WoO) study of ST101, an antagonist of C/EBPβ. CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor that supports glioblastoma (GBM) tumor progression and an immunosuppressive tumor microenvironment (TME) in GBM. C/EBPβ contributes to the immunosuppressive TME by promoting the polarization of macrophages and activated microglia to a pro-tumor M2 phenotype. Previous studies indicate ST101 drives polarization of immunosuppressive M2 tumor-associated macrophages (TAMs) and microglia toward an anti-tumor M1-like phenotype in vitro. A prior phase 2 trial of ST101 monotherapy in 30 patients with recurrent GBM (rGBM) indicated ST101 monotherapy was safe, well-tolerated, and generated meaningful clinical responses, including two partial responses (PR) that lasted a median of one year and a 12-month overall survival (OS) rate of 40%, exceeding the current standard of care, 2 long term partial responses that lasted over one year. The WoO study consisted of patient cohorts with rGBM (n=9) and newly diagnosed GBM (ndGBM; n=9). Patients with rGBM received two to 4 doses of ST101 weekly prior to surgery and continued weekly doses after surgery until disease progression. Patients with ndGBM received 2-3 doses ST101 weekly prior to surgery and received ST101 with chemoradiation and lomustine after surgery until disease progression. The disease control rate (DCR) in the rGBM was 4/9, with 2 PR and 2 patients with stable disease (SD). Among the 8 evaluable patients in the ndGBM arm, the DCR was 7/8 with 2 PR and 2 patients with SD. ST101 was found to cross the blood-brain barrier and be taken into the tumor. Once in the tumor, ST101 engaged with its target C/EBPβ. ST101 was associated with increased CD8+ T cell infiltration into the tumor, increased levels of TAMs with an anti-tumor M1-like phenotype, and increased ratio of M1/M2 TAMs, and these shifts were associated with clinical responses. These data indicate that ST101 monotherapy for rGBM and ST101 in combination with radiotherapy and lomustine for ndGBM are safe and exhibit promising clinical activity by remodeling the immune microenvironment of GBM tumors. GBM is largely resistant to immune checkpoint inhibitors, and these data suggest ST101 may potentially overcome this resistance and enhance the anti-tumor activity of immune checkpoint inhibitors for GBM.

Safety and early efficacy results of a Claudin 18.2-targeting T cell antigen coupler T cell therapy in solid tumors

1472. A phase 1/2 study evaluating the safety and efficacy of autologous TAC T cells in subjects with claudin 18.2+ advanced solid tumors

Ecaterina Dumbrava (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) reported results from TACTIC-3, a phase 1/2 first-in-human study of TAC01-CLDN18.2, an autologous T cell product of T cells targeting CLDN18.2. TAC01-CLDN18.2 was generated with T cell antigen coupler (TAC) technology and contains three domains: an antigen targeting domain targeting Claudin 18.2 on tumor cells, a CD3 binding domain that activates the T cell receptor (TCR), and a transmembrane co-receptor that facilitates intracellular signaling via LCK, mimicking physiological TCR activation. The ongoing phase 1 dose escalation study utilized a 3+3 dose escalation design. Patients with Claudin 18.2-positive solid tumors underwent lymphodepletion followed by infusion with TAC01-CLDN18.2. A second round of depletion followed by infusion with TAC01-CLDN18.2 two years after the first dose was permitted. Of the 6 patients treated with TAC01-CLDN18.2, no dose-limiting toxicities were reported. No cases of cytokine release syndrome were reported, and one patient experienced a grade 1 neurotoxicity that was resolved within 24 hours without intervention. The disease control rate was 83.3%, and target lesions decreased in all 3 patients with pancreatic cancer. One patient with pancreatic cancer with high CLDN18.2 expression experienced an ongoing partial response, and an unconfirmed complete response after receiving a second dose of TAC01-CLDN18.2. TACs were detected in the peripheral blood of most patients 29 days after infusion, and also among patients with pancreatic cancer who responded.  TACs were detected up to 90 days after infusion. Interim results from this phase 1 study suggest that TAC01-CLDN18.2 is well tolerated and produces early signals of clinical activity against CLDN18-2-positive tumors. Enrollment for a disease-specific dose expansion phase 2 trial of TAC01-CLDN18.2 will begin in the near future.

PRAME-targeting TCR-engineered T cell therapy for solid tumors

687. ACTengine IMA203 TCR-T targeting PRAME shows deep and durable anti-tumor activity in heavily pretreated solid cancer patients

Martin Wermke (University Hospital Dresden, Dresden, Germany) presented results from an ongoing Phase 1b trial of ACTengine IMA203, a T cell receptor- (TCR-) engineered T cell (TCR T cell) therapy targeting HLA-A*02:01-presented PRAME peptides. PRAME is a multi-cancer target expressed in a variety of solid tumors. 70 patients with recurrent or refractory solid tumors underwent lymphodepletion and were infused with IMA203. 28 patients were in the dose escalation cohort, and 42 patients in the dose expansion cohort received the recommended phase 2 dose of 1 to10 x 10^9 total TCR-T cells. 41 patients in the dose expansion cohort made up the efficacy population. Patients were heavily pretreated, and the total patient population (n =70) had received a median of 3 prior systemic treatments. 41 patients in the total patient population and 26 patients in the efficacy population had melanoma. IMA203 was well-tolerated. 11% of all patients developed Grade 3 cytokine release syndrome (CRS), and no Grade 4 CRS was observed. Neurotoxicities were infrequent, with 4% of patients experiencing Grade 3 ICANS. No treatment-related deaths occurred, and the maximum tolerated dose was not reached. Responses were observed in a variety of tumors, including cutaneous melanoma (confirmed overall response rate (cORR) 54%), uveal melanoma (cORR 60%), ovarian cancer (cORR 2/4), and synovial sarcoma (cORR 1/3), and almost all patients exhibited disease control 6 weeks after infusion. Increased cell dose and lower tumor burden were significantly associated with clinical activity. Responses were durable; the median duration of response in the melanoma cohort (n=26) was 12.1 months, and some responses lasted over 2 years. The disease control rate of this population was 92%, progression free survival was 6.0 months, and median overall survival was not reached. Due to these promising safety and efficacy data, IMA203 TCR T cell therapy has received a Food and Drug Administration Regenerative Medicine Advanced Therapy Designation in multiple PRAME-expressing cancers. A randomized phase 3 trial, SUPRAME, comparing the clinical activity of IMA203 with investigator’s choice of therapy for unresectable or metastatic cutaneous melanoma is expected to begin in December 2024.

Investigating the effects of the microbiome on immune checkpoint inhibitors and anti-cancer immunity

607. CONSORTIUM-IO: A phase 1 study evaluating a combination of an 11-strain bacterial consortium (VE800) and nivolumab in treatment of select refractory or metastatic cancers

Carolina Lyon De Ana (Vedanta Biosciences, Inc., Cambridge, MA, USA) reported results from CONSORTIUM-IO, a first in-human open-label phase 1 study of VE800, an 11-strain bacterial consortium made from clonal cell banks derived from healthy donors, in combination with nivolumab in patients with anti-PD1-refractory solid tumors. VE800 is an example of a live biotherapeutic product (LBP), a capsule that provides a reliable, readily scalable supply of a defined bacterial consortia, avoiding the varied composition and risk of pathogen transfer associated with fecal microbiota products. Previous studies have indicated VE800 improves the anti-tumor activity of anti-PD-1 treatment in mouse models of cancer. 54 patients enrolled in the study and received VE800 and nivolumab. 20 patients had anti-PD-1 relapsed/refractory melanoma, 20 patients had anti-PD-1-naïve gastric or gastroesophageal junction adenocarcinoma, and 14 patients had anti-PD-1-naïve microsatellite-stable colorectal cancer. Patients received vancomycin to facilitate colonization in the intestine, followed by daily 5X doses of VE800 for a week and then daily 1X doses of VE800 until week 16. Monthly dosing with nivolumab began immediately after vancomycin treatment. The combination of VE800 with nivolumab was safe and well-tolerated. Treatment-related adverse events of all grades occurred in 44.4% of patients, and most were attributed to nivolumab. The objective response rate (ORR) threshold was not met thus the study did not continue to phase 2. ORR was 1.9%, with one patient experiencing a partial response, and some patients experienced extended progression free survival (PFS). Metagenomic sequencing of stool samples indicated that VE800 colonized patients in all cohorts, and colonization was sustained up to three months after the start of VE800 administration. In the melanoma cohort, colonization with 5 or more strains was associated with longer duration of PFS, but this association was not statistically significant. VE800 restored the endogenous microbiome of patients in the melanoma cohort after treatment with vancomycin. While VE800 with nivolumab promoted pro-inflammatory peripheral immune changes, no changes in immunosuppressive cells were observed. Furthermore, observed immune changes did not persist. Results from this study indicate that although VE800 was safe and well-tolerated, it had minimal impact on clinical activity of nivolumab. More studies are needed to understand the effect of the microbiome on immune checkpoint inhibitors and systemic anti-cancer immunity.