P1, N=7, Completed, Masonic Cancer Center, University of Minnesota | Active, not recruiting --> Completed

P1, N=98, Terminated, Fate Therapeutics | Trial completion date: May 2039 --> Sep 2023 | Active, not recruiting --> Terminated | Trial primary completion date: May 2024 --> Sep 2023; The study was terminated by the Sponsor.

P1b, N=0, Withdrawn, Fate Therapeutics

P1, N=98, Active, not recruiting, Fate Therapeutics | Recruiting --> Active, not recruiting | N=552 --> 98

P1, N=3, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Terminated --> Active, not recruiting | Trial completion date: Feb 2023 --> Feb 2024

P1, N=3, Terminated, Masonic Cancer Center, University of Minnesota | N=50 --> 3 | Trial completion date: Oct 2025 --> Feb 2023 | Suspended --> Terminated | Trial primary completion date: Oct 2025 --> Feb 2023

P1, N=50, Suspended, Masonic Cancer Center, University of Minnesota | Recruiting --> Suspended

P1, N=552, Recruiting, Fate Therapeutics | N=285 --> 552

Conditioning chemotherapy (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 on Days -5 to -3) is administered followed by a single dose of FT596 as monotherapy (Regimen A) or combined with rituximab (R) 375 mg/m 2 (Regimen B1) or obinutuzumab 1000 mg/m 2 (Regimen B2) on Day -4. FT596 monotherapy or in combination with R was well tolerated and demonstrated activity in pts with R/R BCL, including in pts previously treated with CAR T-cell therapy. Administration of a second FT596 treatment cycle was well tolerated with evidence of continuing clinical benefit. Dose escalation of FT596 is ongoing.

Treatments for B - cell malignancies have improved over the past several decades with clinical application of the CD20-specific antibody rituximab and chimeric antigen receptor (CAR) T cells targeting CD19. Further, these data suggest that iDuo NK cells may have an additional advantage over anti-CD19 CAR T cells by discriminating between healthy and malignant B cells. The first iDuo NK cell, FT596, is currently being tested in a Phase I clinical trial (NCT04245722) for the treatment of B-cell lymphoma.

P1, N=285, Recruiting, Fate Therapeutics | N=123 --> 285 | Trial completion date: Apr 2037 --> May 2039 | Trial primary completion date: Apr 2022 --> May 2024

A transient elevation of interleukin-6 levels was detected at all dose levels, 2-4 hours post-dose, which returned to baseline levels after 24 hours. These results emphasize the promise of bispecific innate cell engagers as an alternative cancer therapy and demonstrate the potential for AFM24 to effectively target tumors expressing varying levels of EGFR, regardless of their mutational status.Abbreviations: ADA: antidrug antibody; ADCC: antibody-dependent cell-mediated cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; AUC: area under the curve; CAR: chimeric-antigen receptor; CD: Cluster of differentiation; CRC :colorectal cancer; ECD: extracellular domain; EGF: epidermal growth factorEGFR epidermal growth factor receptor; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; Fc: fragment, crystallizableFv variable fragment; HNSCC: head and neck squamous carcinomaIL interleukinm; Ab monoclonal antibody; MOA: mechanism of action; NK :natural killer; NSCLC: non-small cell lung cancer; PBMC: peripheral blood mononuclear cell; PBS: phosphate-buffered saline; PD: pharmacodynamic; ROCK: redirected optimized cell killing; RSV: respiratory syncytial virus; SABC: specific antibody binding capacity; SD: standard deviation; TAM: tumor-associated macrophage; TKI: tyrosine kinase inhibitor; WT: wildtype.

Our results suggest that KIR3DL2+ and HLA-A3/11+ with FCGR3A-158V markers lead to enhanced Isa-dependent NK-mediated cytolysis against MM cells and results in improved PFS in patients with RRMM treated by Isa-Len-Dex. Moreover, the presence of KIR2DL1+ and HLA-C2C2+ identifies patients who may have a lower response to Isa-Len-Dex therapy linked to a reduced NK-mediated ADCC. These biomarkers could potentially identify, via precision medicine, patients more likely to respond to Isa-Len-Dex immunotherapy.

Background Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition CTX in metastatic/locally advanced, treatment-na ve, HER2+ GEJ/GC patients.

Finally, MEK inhibitors were identified by CMap as the prospective therapeutic drugs for CYP2D6 deletion. These analyses identified novel resistance mechanisms to systemic NSCLC treatments and had significant implications for the development of new treatment strategies.

We identify AFM13 as a promising combination with cytokine-activated adult blood or cord blood NK cells to treat CD30+ hematologic malignancies, warranting clinical trials with these novel combinations.

Moreover, we are working on combining base editing technology to knockout inhibitory genes and create non-cleavable CD16a in NK cells in combination with our CAR constructs. Ultimately, our goal is to go beyond simple CD133 CAR and develop a more effective targeted therapy for AVPC.

These data revealed that co-DTCs showed up-regulation of cell proliferation related genes compare to DTCs, and some ATCs had different immune cell profiles . co-DTCs showed an intermediate immune cell profile between ATC and DTC . Biological profiling of ATCs, DTCs and co-DTCs may help to understand the developmental mechanism of ATCs .

The antibody has been engineered for increased binding to activating Fcγ receptor IIIA (CD16A) and decreased binding to inhibitory Fcγ receptor IIB (CD32B) relative to trastuzumab with the aim of improving response rates. Based on the results of the phase III SOPHIA trial margetuximab has been approved in the USA for use in combination with chemotherapy as treatment of previously-treated metastatic HER2-positive breast cancer. This article summarizes the milestones in the development of margetuximab leading to this first approval.

Importantly, we confirmed in ex vivo experiments, the depletion of these immunosuppressive cells by MEN1112/OBT357. Overall, our data demonstrate that MEN1112/OBT357 is a novel antibody with potent ex vivo activity against blast cells in AML and MDS patients, suggesting a potential contribution of MEN1112/OBT357 in altering the immunosuppressive environment in the bone marrow niche.

To confirm selectivity and avoidance of immunoglobulin interference with functional output, various in vitro cellular cytotoxicity assays were conducted with IgG1 to confirm that hnCD16 requires crosslinking to elicit ADCC while maintaining full potentiation of CAR function. Additional in vitro and in vivo studies are ongoing and will be presented.Collectively, the data demonstrates that CAR-iT cells can be further modified with hnCD16 Fc receptor to elicit ADCC and the combination of CAR and hnCD16 is a unique approach to tackling tumor heterogeneity often found in bulky tumors.

These studies revealed that mAb therapy efficacy positively correlates with higher affinity binding to CD16A. Approaches to enhance tumor antigen targeting by NK cells by modifying the Fc portion of antibodies or the FcR on NK cells are the focus of this review.

FCGR1A may be a potential prognostic biomarker and related to immune infiltration levels in diverse cancers, especially in CESC, CHOL, KIRC, and SKCM. Besides, FCGR1A may be involved in the activation, regulation, or induction of immune cells and diverse physiological and pathological processes.

Research Funding: MacroGenics, Inc Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. Part 2 of cohort B consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either retifanlimab or tebotelimab, depending on results from part 1; with 250 patients each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival.

Finally, the use of primary CD56 cells in ADCC experiments comparing glycoengineered variants of trastuzumab was conclusive to test the limits of this type of ex vivo system. Although the effector functions of CD56 cells reflected to some extent the in vitro receptor binding properties and cytolytic activity data using NK92 cells, as previously published, reaching a functional avidity plateau could limit their use in a quality control framework.

In this study we investigated transcriptomic profiles of CLL/RS-involved nodal tissue using samples from a clinical trial cohort of refractory CLL and RS patients treated with Pembrolizumab (NCT02332980)... Our study indicates that ibrutinib-resistant, RS-involved tissues are characterized by downregulation of genes in B cell activation, but with PRKCB and TERT upregulation. Furthermore, RS-involved nodal tissues display the increased expression of genes involved in myeloid/monocytic regulation in comparison with CLL-involved nodal tissues. These findings implicate that differential therapies for RS and CLL patients need to be adopted based on their prior therapy and gene expression signatures.

The median number of prior therapies was 4 (1-11) and 4 subjects had progressed on brentuximab vedotin. In addition, biological changes in NK infiltration and activation in the PB and tissue biopsy correlated with response. These data are the first to demonstrate that innate cell engagers modulate NK and T cell populations in the peripheral blood and tumor from patients and to determine that such changes are associated with patient benefit.

Induced pluripotent stem cell (iPSC)-derived immune effector cells offer distinct advantages over existing patient- and donor-derived therapeutic approaches, including the use of a clonal master engineered iPSC line as a renewable source for the mass production of immune cells, which are available off-the-shelf for broad patient access...FT596 is currently being investigated as a monotherapy and in combination with the anti-CD20 mAbs rituximab and obinutuzumab in a multicenter, Phase I clinical trial for the treatment of relapsed/refractory B-cell lymphoma and chronic lymphocytic leukemia...The patient received fludarabine and cyclophosphamide lympho-conditioning followed by a single administration of 30 million cells of FT596 as monotherapy...Additional clinical, pharmacokinetic, and pharmacodynamic data from this patient will be provided at the time of the meeting. The Phase I trial is ongoing and is registered on clinicaltrials.gov: NCT04245722.

INTRODUCTION: The outcome of patients (pts) with classical Hodgkin Lymphoma (cHL) experiencing relapse after high dose chemotherapy, brentuximab vedotin (BV) and anti-PD1 antibody (Ab) treatment is poor and in most patients the duration of the response to this treatment is rather short. Treatment with AFM13 was well tolerated and showed modest activity in heavily pretreated pts. The responses documented in arm C qualified this arm with continuous AFM13 application over 5 days for further evaluation in trial stage 2 and thus indicated its potential. However, the trial was prematurely stopped due to low recruitment leading to the conclusion that the acceptance of the application schedule is extremely important.

The engineered NK cells used in our study were derived from genetically edited and clonally derived induced pluripotent stem cells (iPSCs) through a series of stepwise differentiation stages (figure 2)...In Figure 3, using an in vitro Delfia® ADCC assay, we show that iNK-CD64/16A cells mediated ADCC against SKOV3 cells, an ovarian adenocarcinoma cell line, in the presence of the anti-HER2 therapeutic mAb trastuzumab (Herceptin) or anti-EGFR1 therapeutic mAb cetuximab (Erbitux), when either added to the assay or pre-adsorbed to the iNK cells (figure 3)...iNK-CD64/16A cells were added with or without pre-adsorbed Rituxan and the assay was performed in 10% AB serum...The various recombinant CD64 constructs were initially expressed in NK92 cells (lacks expression of endogenous FcγRs) (figure 7)...Our goal is to utilize this docking approach to pre-absorb mAbs to iNK cells for adoptive cell therapy. The mAbs would thus provide tumor-targeting elements that could be exchanged as a means of preventing tumor cell escape by selectively and easily altering NK cell specificity for tumor antigens.