P2; N=171; Active, not recruiting; Sponsor:Immutep S.A.S.

P2, N=40, Recruiting, Maria Sklodowska-Curie National Research Institute of Oncology

P2; Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2023 --> Mar 2024

Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. Overall survival was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2- MBC.

No abstract available

Subcutaneously administered efti plus avelumab was well tolerated, and efti of 30 mg was determined to be RP2D. The activity is promising and warrants further investigation in future phase II trials.

P2, N=189, Active, not recruiting, Immutep S.A.S. | Trial completion date: Nov 2023 --> Nov 2024

GEP analysis showed upregulated expression of genes related to T-cell functions, cytotoxicity functions, cytotoxic cells, or TH1 cells which are more pronounced in pts with PR/CR. Conclusions Significant early and sustained increases of circulating biomarkers and ALC substantiate the systemic stimulation via the APC activator efti and show that repeated minimally-invasive liquid biopsies, i. e. , blood samplings, are key in detecting this systemic stimulation.

Not applicable

P1, N=110, Recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | N=45 --> 110 | Trial completion date: Jun 2024 --> Sep 2025 | Trial primary completion date: Jun 2024 --> Sep 2025

P2; Trial primary completion date: Jul 2023 --> Dec 2023

To date, two LAG-3-directed agents (eftilagimod alpha and relatlimab) have been approved in combination with programmed death-1 (PD-1) inhibitors in the setting of advanced solid tumors. In this review, we discuss the structure of LAG-3, its mechanism of action, and its interaction with its ligands. We also shed light on the emerging treatments targeting LAG-3 for the treatment of solid tumors.

Correlation between tissue or blood-based biomarkers and clinical outcomes will be explored. Enrollment for the study is ongoing in Poland.

Methods Pts with 1st line advanced or metastatic NSCLC adenocarcinomas (non-squamous) receive carboplatin AUC5 / pemetrexed 500 mg/m2 q3w 4 cycles followed by optional pemetrexed 500 mg/m2 q3w maintenance plus pembrolizumab 200 mg q3w combined with s.c. efti (30 mg) (q2w for 24 weeks; thereafter q3w till week 52). Median follow up: 8.3 months, median OS: not reached. Conclusions To date, 30 mg efti combined with SOC appears to be feasible and safe with promising signals of efficacy, so that the trial was amended for inclusion of further 30 pts.

Conclusions E + P shows encouraging OS results in line with excellent ORR, PFS and DOR in 1st line NSCLC overall and in all PD-L1 subgroups. This combination warrants further late-stage clinical investigation.

Sponsored by Pharmaceutical/Biotech Company, Immutep S.A. Clinical Trial Registration Number: NCT03625323. Efti + pembrolizumab is safe, showing encouraging antitumor activity in platinum and partially cetuximab pre-treated, 2nd line HNSCC patients. TACTI-003 (NCT04811027) a randomized study in 1st line HNSCC is currently recruiting. Response by iRECIST: Clinical trial information: NCT03625323.

Key inclusion criteria: Pts with either a) HR+ and HER2-neg/low and endocrine therapy-resistant MBC or b) TNBC not eligible for anti-PD-1-based therapy. Pts must have measurable disease, ECOG PS 0-1 and no prior chemo for metastatic disease.

Key inclusion criteria: Pts with either a) HR+ and HER2-neg/low and endocrine therapy-resistant MBC or b) TNBC not eligible for anti-PD-1-based therapy. Pts must have measurable disease, ECOG PS 0-1 and no prior chemo for metastatic disease.

P1, N=0, Withdrawn, Immutep S.A.S. | N=24 --> 0 | Not yet recruiting --> Withdrawn

P2/3, N=849, Recruiting, Immutep S.A.S. | Not yet recruiting --> Recruiting

The remaining 50% of metastasizing SCTs were CTNNB1-wild-type and harbored alterations in TP53, MDM2, CDKN2A/CDKN2B, and TERT pathways. These findings suggest that aggressive SCTs can arise from progression of CTNNB1-mutant benign SCTs, or from CTNNB1-wild type tumors with alterations of TP53, cell cycle regulation, and telomere maintenance pathways.

Herein, a tactical nanomissile (TALE), equipped with a guidance system (PD-L1 monoclonal antibody), ammunition (mitoxantrone, Mit), and projectile bodies (tertiary amines modified azobenzene derivatives), is designed as a neoadjuvant chemo-immunotherapy setting, which aims at targeting tumor cells, and fast-releasing Mit owing to the intracellular azoreductase, thereby inducing immunogenic tumor cells death, and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system...Moreover, this approach provokes a robust systemic immune response and immunological memory, as evidenced by preventing 83.3% of mice from postsurgical metastasis or recurrence in the B16-F10 tumor mouse model. Collectively, our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.

The usage of these substances in the treatment of solid tumors is being investigated. The present review discusses the direct and indirect influence that TLR7/8 agonists, such as imiquimod, imidazoquinolines and resiquimod have on neoplastic cells and their promising role as adjuvants in anticancer vaccines.

P2/3, N=849, Not yet recruiting, Immutep S.A.S.

Most common (>15%) adverse events were decreased appetite (33%), dyspnea (31%), cough (28%), asthenia (22%), fatigue (19%), arthralgia (17%) and weight decreased (17%). Conclusions Efti + pembrolizumab is safe and shows encouraging signs of antitumor activity in NSCLC pts resistant to PD-1/PD-L1 inhibitors, warranting further investigation.

In SPOPMT PCs, inactivation of APC is a common event and associated with more aggressive disease (higher metastatic potential and faster progression to castration resistance). This observation may help identify SPOPMT PC patients who are at higher risk for early castration resistance and could benefit from more intensive treatment.

Sotiga induced dramatic changes in the tumor microenvironment including increased frequency of activated T cells and APCs, and decreased frequency of Tregs. A distinct signature of T cell infiltration in baseline tumor biopsies was observed in patients who achieved a pCR versus those who did not, potentially identifying patients that may benefit from this novel treatment strategy.

30 mg efti appears to be feasible and safe.

Some first-line cytotoxic chemotherapics, e.g. doxorubicin, paclitaxel and oxaliplatin, induce activation of the immune system through immunogenic cell death (ICD). Bona fide ICD induction by CA was confirmed by vaccination of C57BL/6 mice with CA-treated cells which activated antigen-presenting cells and T lymphocytes and stimulated antitumor activity. CA induces bona fide immunogenic cell death on melanoma.

When combined with a PD-1 checkpoint inhibitor, the soluble LAG3 drug eftilagimod alpha activates antigen-presenting cells, offering deep and durable responses against non-small cell lung cancer. Even patients whose tumors express low levels of PD-L1 experienced an anticancer benefit.

Using lipoplex (Lipo-PEG-PEI-complex, LPPC) encapsulated doxorubicin (DOX) and carrying CpG oligodeoxynucleotide; the transdermally administered nano-liposomal drug complex (LPPC-DOX-CpG) would have high cytotoxicity and immunostimulatory activity to suppress systemic metastasis of melanoma...Furthermore, NGS analysis revealed IFN-γ and NF-κB pathways were triggered to recruit and activate the antigen-presenting-cells and effecter cells, which could activate the anti-tumor responses as the major mechanism responsible for the therapeutic effect of LPPC-DOX-CpG. Finally, we have successfully proved transdermal LPPC-DOX-CpG as a promising penetrative carrier to activate systemic anti-tumor immunity against subcutaneous and metastatic tumor.

P2 | "Early & sustained increases of circulating CXCL-10 & IFN-gamma levels were observed. Conclusions E + P is safe & shows encouraging antitumor activity in 1st line metastatic NSCLC patients unselected for PD-L1, warranting late-stage clinical investigation."

The QFN-PTT-treated mice exhibited significantly elongated survival time, and gained strong anti-tumor immune memory to prevent tumor metastasis and recurrence. Thus, this work provided a simple and versatile photothermic agent, and it has important implications for designing effective and translationally feasible photosensitizers for PTT.

Furthermore, an association between RTK/MAPK pathway activity and susceptibility to HDAC inhibition was observed. This finding was further validated in patient-derived organoids from gastric adenocarcinoma, thus identifying a novel treatment approach for RTK/MAPK pathway altered gastric cancer patients.

CDX-301 will be discontinued after 2 cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Key eligibility criteria are unresectable stage III or stage IV TNBC (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line metastatic treatment setting (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre- treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites (NCT05029999).

Conclusions We have generated bispecific antibodies specific to both CD40 and 5T4 that could achieve APC activation only in 5T4-expressing tumor microenvironment and demonstrate anti-tumor efficacy without inducing systemic toxicity. The preclinical data warrant further development of 5T4 x CD40 bispecific antibody as a potential therapeutic option for solid tumor.

Secondary EPs include overall survival, ORR according to iRECIST, time to and duration of response, disease control rate, progression-free survival, the occurrence of anti-efti -specific antibodies, safety, and quality of life. Exploratory endpoints comprise biomarkers.

However, when larger tumors were treated, the effects seen at 2 d were diminished, even with an additional treatment. These results provide a working platform for further rational design of focused ultrasound and immunotherapy combinations in poorly immunogenic cancers.

P1, N=24, Not yet recruiting, Immutep S.A.S. | Trial completion date: Feb 2024 --> Feb 2026 | Trial primary completion date: Jun 2023 --> Jun 2025

Next, to verify the critical role of CD8 T cells in suppressing melanoma development, we transplanted CD8 T cells from immunised mice to B16F10 tumor-bearing mice and discovered that the survival rate of tumor-bearing mice was significantly prolonged. In summary, our experimental results indicate that CHR can be used as a potential adjuvant to enhance antigen immunogenicity, inhibit B16F10 tumor growth in mice and improve tumor immune response.