Innate Pharma (France)

Natural killer (NK) cells are cytotoxic and cytokine-producing innate lymphocytes with established roles in antiviral and antitumor immunity. In recent years, the biology of NK cells has been exploited in innovative cancer immunotherapies, leading to clinical advances including allogeneic NK cell infusions, chimeric antigen receptor NK cells, and NK cell engager technologies. These studies pave the way to explore how advances in NK cell-based immunotherapies could be leveraged outside of oncology to selectively target pathogenic cells and restore tissue homeostasis in viral infections, neurodegenerative disorders, autoimmunity, and transplantation medicine.

NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including those with low CD20 density. Whereas it presented reduced toxicities compared with those commonly associated with T cell therapies, CD20-NKCE-IL2v showed greater killing efficacy over a T cell engager targeting CD20 in in vitro preclinical models. CD20-NKCE-IL2v also increased the cell surface expression of NK cell-activating receptors, leading to activity against CD20-negative tumor cells. In vivo studies in nonhuman primates and tumor mouse models further validated its efficacy and revealed that CD20-NKCE-IL2v induces peripheral NK cell homing at the tumor site. CD20-NKCE-IL2v emerges as a potential alternative in the treatment landscape of B-NHL.

BackgroundNectin-4 is overexpressed in multiple solid tumors with high unmet medical need, such as urothelial carcinoma (UC), esophageal cancer, non-small cell lung cancer, or triple-negative breast cancer. Enfortumab vedotin (EV), a Nectin-4-targeting antibody-drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload, has been approved for the treatment of UC, which exhibits the highest Nectin-4 expression. To address cancers with lower Nectin-4 expression and enhance the therapeutic index, we developed IPH45, a differentiated anti-Nectin-4 ADC conjugated to exatecan with a cleavable hydrophilic linker, and a drug-to-antibody ratio (DAR) of 8.MethodsIn vitro studies were conducted to investigate the modes of action of IPH45, including binding, internalization, cytotoxicity, and bystander effect. In vivo studies were conducted using syngeneic mouse models, cell line-derived xenografts, and patient-derived xenografts (PDXs) from various indications to assess the activity of IPH45.ResultsIPH45 binds to Nectin-4 on a panel of cell lines and primary tumors that express the target. Upon binding to its target, IPH45 is internalized, leading to the killing of Nectin-4 expressing cancer cells. While IPH45 shows no off-target activity in vitro, it exhibits a potent bystander killing effect on Nectin-4 negative cells when mixed with Nectin-4 positive ones, related to the exatecan payload. The in vivo capacity of IPH45 to eliminate cancer cells with low Nectin-4 expression, in addition to the bystander effect, results in IPH45 efficacy in PDX models with various levels of Nectin-4 expression. IPH45 also induces activity in PDX models from different indications, including UC and prostate cancer, as well as in cell line-derived xenografts from breast cancer. Moreover, IPH45 shows efficacy in models resistant to MMAE. In syngeneic mouse models, the combination of IPH45 and an anti-PD-1 antibody induces synergistic anti-tumor activity in both EV-sensitive and EV-refractory models.ConclusionsIPH45 strong internalization and bystander effect enable to achieve an efficient anti-tumor activity in models regardless of Nectin-4 expression. The activity of IPH45 in various indications and its enhanced anti-tumor activity in combination with anti-PD-1 therapies in preclinical models support its development beyond UC. IPH45 is progressing towards the clinic with IND planned in 2024.

7082 Background: Cutaneous T-cell lymphoma (CTCL) is a rare form of non-hodgkin’s lymphoma. The most common type of CTCL is Mycosis Fungoides (MF) accounting for 50-60% of cases, while Sezary Syndrome, the leukemic variant of MF accounts for 2-5% of cases. Extracutaneous involvement occurs mainly in lymph nodes or blood; 25% of patients (pts) are diagnosed at advanced stage with a 5-year survival of 15-25%. KIR3DL2 is a killer immunoglobulin-like receptor, expressed in 90% of SS pts, and 50% of MF pts. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. Methods: TELLOMAK is an international, open-label, multi-cohort phase 2 trial (NCT03902184). MF pts who had received at least 2 prior systemic therapies were allocated to different cohorts according to KIR3DL2 expression in skin. Lacutamab 750 mg is administered as an intravenous infusion until disease progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) by global response score based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to International Consensus criteria (Olsen 2011; sensitivity analysis vs revised Olsen 2022). Secondary endpoints included other efficacy endpoints, safety, and quality of life. Here we report data of all MF patients, and according to KIR3DL2 status. Results: At the data cutoff of October 13, 2023, recruitment was completed, with 107 pts enrolled. Median age was 62 years. Median number of previous systemic lines was 4 (range: 1-14). Median follow-up was 11.8 months (m) (95% CI 9.9-13.8). ORR was 16.8% (CI 10.9, 25.0; Olsen 2011), and 22.4% (CI 15.6, 31.2; Olsen 2022), response in skin and blood was 29.0% (CI 21.2, 38.2) and 40.0% (CI 24.6, 57.7) respectively. Median time to response was 1.0 months and median PFS 10.2m (CI 6.5, 16.8). Among the KIR3DL2 ≥1% pts (N=48), ORR was 20.8% (CI 11.7,34.3; Olsen 2011), and 29.2% (CI 18.2, 43.2; Olsen 2022), response in skin and in blood was observed in 33.3% (CI 21.7, 47.5) and 41.2% (CI 21.6, 64.0) respectively. Median time to response was 1.0 month and median PFS was 12.0 m (CI 5.6, 20.0). Median duration of response was not reached. Grade ≥ 3 Treatment-related (TR) Treatment-Emergent Adverse events (TEAEs) were observed in 4/107 (3.7%) pts, serious TR TEAEs were observed in 4/107 (3.7%) pts and 3/107 (2.8%) pts discontinued study drug due to TR TEAEs. The most common (>10%) TR TEAEs were fatigue (11.2%), nausea (11.2%), asthenia (10.3%), and arthralgia (10.3%). Conclusions: The data from the heavily pre-treated MF population enrolled to the TELLOMAK study confirms promising clinical activity of lacutamab regardless of KIR3DL2 expression, with a favorable safety and tolerability profile. These data support the further development of lacutamab in an effort to bring improved treatments to patients with CTCL. Clinical trial information: NCT03902184 .

Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19. FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study. Twelve clinical sites in France (ICU and general hospitals). Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3. Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2. We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified. In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367).

Natural killer (NK) cells are known to be able to kill established tumor cell lines, but important caveats remain regarding their roles in the detection and elimination of developing primary tumors. Using a genetic model of selective ILC1 and NK cell deficiency, we showed that these cells were dispensable for tumor immunosurveillance and immunoediting in the MCA-induced carcinogenesis model. However, we were able to generate primary cell lines derived from MCA-induced tumors with graded sensitivity to NK1.1+ cells (including NK cells and ILC1). This differential sensitivity was associated neither with a modulation of intratumoral NK cell frequency, nor the capacity of tumor cells to activate NK cells. Instead, ILC1 infiltration into the tumor was found to be a critical determinant of NK1.1+ cell-dependent tumor growth. Finally, bulk tumor RNAseq analysis identified a gene expression signature associated with tumor sensitivity to NK1.1+ cells. ILC1 therefore appear to play an active role in inhibiting the antitumoral immune response, prompting to evaluate the differential tumor infiltration of ILC1 and NK cells in patients to optimize the harnessing of immunity in cancer therapies.