P1, N=230, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Feb 2025 --> Jun 2025 | Trial primary completion date: Feb 2025 --> Jun 2025

P1, N=130, Active, not recruiting, NGM Biopharmaceuticals, Inc | Recruiting --> Active, not recruiting

P1, N=280, Recruiting, Biond Biologics | Not yet recruiting --> Recruiting

P1, N=106, Active, not recruiting, Immune-Onc Therapeutics | Recruiting --> Active, not recruiting

P1, N=22, Completed, Immune-Onc Therapeutics | Active, not recruiting --> Completed | N=200 --> 22

In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T cell immunotherapy is promising against tumor cells and immunosuppressive tumor microenvironment in MM.

P1, N=13, Completed, Presage Biosciences

P1, N=230, Active, not recruiting, Merck Sharp & Dohme LLC | Phase classification: P1b --> P1

P1, N=280, Not yet recruiting, Biond Biologics

P1, N=130, Recruiting, NGM Biopharmaceuticals, Inc | N=79 --> 130 | Trial completion date: Dec 2024 --> Mar 2026 | Trial primary completion date: Feb 2024 --> Jul 2025

P1, N=106, Recruiting, Immune-Onc Therapeutics | Trial completion date: May 2025 --> Jan 2027 | Trial primary completion date: Dec 2023 --> Jan 2026

P1, N=12, Terminated, Merck Sharp & Dohme LLC | N=35 --> 12 | Active, not recruiting --> Terminated; Business Reasons

P1, N=35, Active, not recruiting, Merck Sharp & Dohme LLC | Phase classification: P1b --> P1 | Trial completion date: Aug 2025 --> Dec 2023 | Trial primary completion date: Aug 2025 --> Dec 2023

P1, N=200, Active, not recruiting, Immune-Onc Therapeutics | Recruiting --> Active, not recruiting

P1, N=8, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital

P1, N=200, Recruiting, Immune-Onc Therapeutics | Trial primary completion date: Apr 2023 --> Apr 2024

P1b, N=230, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

In combination therapy, 1 AML patient with high LILRB4 expression who was refractory to azacitidine and venetoclax based combination therapy achieved CR, ongoing at 7+ months. IO-202 is safe and well tolerated as monotherapy and in combination with AZA. Encouraging responses, including monotherapy activity, ongoing CR in an AML patient with high LILRB4 expression, and PR and Optimal Marrow Response in CMML patients, were observed. PD biomarker data supported proposed MOA.

P1b, N=35, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: May 2024 --> Aug 2025 | Trial primary completion date: May 2024 --> Aug 2025

P1, N=15, Recruiting, Presage Biosciences | N=24 --> 15

In both whole blood cytokine release assays and in TDCC assays in which cytokine secretion was measured after target engagement, induction of TNF-α, IL-6, IFN-γ, and IL-2 by NGM936 was considerably lower than that induced by a vibecotamab biosimilar (CD123 x CD3). Finally, NGM936 induced a dose-dependent depletion of circulating tumor cells in a xenograft model in which irradiated, immunodeficient NSG mice were engrafted with human PBMCs and human ILT3+ AML cells. NGM936 thus represents a promising new treatment strategy for monocytic AML, with the potential to eliminate monocytic leukemia cells while minimizing the myelotoxicity associated with ablation of healthy bone marrow.

Our work represents the first evidence and rationale for clinical development of NGM936 surrogate antibody an ILT3-targeted immunotherapy as a viable therapeutic approach for MM cell killing. These data suggest that targeting ILT3 is an effective and safe therapeutic approach in MM.

P1b, N=230, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Oct 2024 --> Feb 2025 | Trial primary completion date: Oct 2024 --> Feb 2025

P2, N=120, Recruiting, Merck Sharp & Dohme Corp. | N=60 --> 120

P1, N=24, Recruiting, Presage Biosciences | N=36 --> 24

P1b, N=230, Recruiting, Merck Sharp & Dohme Corp. | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Oct 2024

Taken together, PRMT5 plays an important role in the invasion of AML, which acts via regulating the expression of LILRB4. PRMT5 could act as a potential therapeutic candidate for AML.

Limited data suggest that short-lived remissions can be obtained employing CPX-351 or venetoclax-based lower intensity combination therapy. Promising future strategies include repurposing cladribine, exploiting the supportive role of dendritic cell subsets with anti-CD123 therapies, MCL-1 inhibition, dual MEK/PLK1 inhibition, FLT3 inhibition in RAS-mutated and CBL-mutated subsets, and immune therapies targeting novel immune checkpoint molecules such as the leukocyte immunoglobulin-like receptor B4 (LILRB4), an immune-modulatory transmembrane protein restrictively expressed on monocytic cells. The successful management of an entity as unique as CMML-BP will require a cooperative, concerted effort to design and conduct clinical trials dedicated to this rare form of sAML.

The highest and lowest 10% expression levels of AHR in all samples in Beat AML were evaluated for mutation profiles. Ranking the top 18 mutations based on frequency we found an enrichment of FLT3 mutations in the high AHR expression group compared to the lower expression group (Figure 1A). ELN risk did not correlate with AHR expression however FAB classification M0/M1 and M4/M5 monocytic subtypes had higher AHR expression than M3 FAB subtype (Figure 2A).

CCR1, IL12RB1, LILRB4 and SEMA4A were upregulated by the treatment with Bortezomib or Venetoclax that conversely, decreased BCMA expression in MM U266 cells. This study suggests the contribution of an altered MM surfaceome to disease development and may lead to potential novel immunotherapeutic approaches for high-risk MM. References Perna F et al., Cancer Cell 2017 Perna F. Molecular Therapy 2021 Dong C et al., in press Oncogene 2021

Except for the mRNA levels of Cd74 and Clec7a which were increased at HCS when Herceptin was used in both prophylactic and therapeutic regimens, the levels of other described mRNAs were reduced. These novel findings show that Herceptin ameliorates the clinical score in EAE mice and are the first to investigate in detail the differential gene expression post-treatment with the drug.

This is the first systemically examination of the LILRB family expression on a variety of immune cells from both peripheral blood and microenvironment in HCC patients. The specific increasing expression of LILRB on immune cells may regulate innate and adaptive immune and impact on HCC progression. Our findings justify further investigation of LILRB function in HCC.

Blockade of B4-FN binding such as with B4 antibodies or a recombinant FN30-Fc fusion protein paradoxically ameliorated autoimmune disease in lupus-prone BXSB/Yaa mice. These unexpected nature of the B4-FN checkpoint in autoimmunity is discussed, referring to its potential role in tumor immunity.

LILRB4-/- genotype or LILRB4 blockade increased tumor immune infiltrates and the effector (Teff) to regulatory (Treg) T cell ratio and modulated phenotypes of TAMs toward less suppressive, CD4+ T cells to Th1 effector, and CD8+ T cells to less exhausted. These findings reveal that LILRB4 strongly suppresses tumor immunity in TME and that alleviating that suppression provides antitumor efficacy.

Finally, in combination with anti-programmed cell death protein 1 (PD1), ILT3 blockade enhanced T cell activation as assessed by IFN-γ secretion. Implications: These results suggest that ILT3 expressed on M-MDSCs has a role in inducing immunosuppression in cancer and that antagonism of ILT3 may be useful to reverse the immunosuppressive function of M-MDSCs and enhance the efficacy of immune checkpoint inhibitors.

These results indicate that inhibition of Th1 and Th17 development provides effective suppression of EAE and suggests the feasibility of a clinical approach based on the use of ILT3.Fc for treatment of MS. Furthermore, our results open the way to further studies on the effect of the human ILT3.Fc protein in murine experimental models of autoimmunity and cancer.

Major exclusion criteria include: 1) HSCT within 60 days, on calcineurin inhibitors, or chronic GVHD; 2) chemotherapy, radiotherapy, or investigational agents within 7 days; 3) significant cardiac disease; 4) active infection; 5) uncontrolled CNS leukemia; and 6) hyperleukocytosis ( > 25 x 109/L, although hydroxyurea is permitted). If there is a >80% probability of DLTs being > 20%, the study will be paused to further evaluate the safety findings. A planned protocol amendment will evaluate combination therapies with IO-202, including IO-202 + azacitidine.

The co-expression of LILRB1/LILRB4 outperformed other myelomonocytic markers as a highly sensitive and specific marker for monocytes at all stages of maturation and could reliably distinguish M-AML from NM-AML. LILRB4 additionally represents a novel therapeutic target for treating M-AML.

FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.

Given current modest results with immunotherapy in myeloid malignancies, further investigation of LILRB4 as an immune checkpoint inhibitor target is needed. With the positive correlation between LILRB4 and CTLA-4 expression, combining anti-LILRB4 and anti-CTLA-4 agents may be a novel therapeutic approach in myeloid malignancies that warrants larger studies.