P1, N=7, Completed, Nordic Nanovector | Phase classification: P1b --> P1

P1/2, N=46, Terminated, Genmab | N=182 --> 46 | Trial completion date: Sep 2025 --> Jul 2023 | Recruiting --> Terminated | Trial primary completion date: Sep 2023 --> Nov 2022; Due to strategic evaluation of GEN3009 within context of Genmab's portfolio, decision not based on any safety or regulatory concerns.

P1/2, N=182, Recruiting, Genmab | Trial completion date: Apr 2025 --> Sep 2025 | Trial primary completion date: Dec 2023 --> Sep 2023

P1a/1b, N=110, Recruiting, Qilu Puget Sound Biotherapeutics (dba Sound Biologics) | Not yet recruiting --> Recruiting

P1/2, N=182, Recruiting, Genmab | N=120 --> 182 | Trial completion date: May 2023 --> Apr 2025 | Trial primary completion date: Nov 2022 --> Dec 2023

P1a/1b, N=110, Not yet recruiting, Qilu Puget Sound Biotherapeutics (dba Sound Biologics)

Besides, some patients relapsed after anti-CD19 CAR-T cell therapy, which possibly were due to limited CAR-T cells persistence, CD19 antigen escape or antigen down-regulation. Quite a few new antigen-targeted CAR-T products and new-generation CAR-T, for example, CD20-targeted CAR-T, CD79b-targeted CAR-T, CD37-targeted CAR-T, multi-antigen-targeted CAR-T, armored CAR-T and four-generation CAR-T are developing rapidly to figure out these deficiencies.

RASGRP2 was abnormally expressed in lung adenocarcinoma and correlated with the infiltration level of immune related cells, which might influence the efficacy of immunotherapy.

In the absence of myeloma cells, lenalidomide and pomalidomide induce CD4 T cell secretion of IL-2 and indirect activation of Natural Killer (NK) cells...Furthermore, combination treatment of IMiDs and myeloma-targeting monoclonal antibodies eg. daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7), checkpoint inhibitors, or bispecific T cell engagers showed synergistic effects, mainly via enhanced T and NK cell dependent cellular toxicity and T cell proliferation. Conversely, the corticosteroid dexamethasone can impair the immune modulatory effects of IMiDs, indicating that careful choice of myeloma drugs in combination with IMiDs is key for the best anti-myeloma therapeutic efficacy. This review presents an overview of the role for T cells in the overall anti-myeloma effects of immunomodulatory drugs.

The bi-specific hCD37-CD19 significantly inhibited Raji xenograft tumor growth and prolonged mouse survival in NOD scid gamma mouse (NSG) mouse model. This study demonstrates that novel humanized CD37 and humanized CD37-CD19 CAR-T cells specifically targeted either CD37 positive or CD37 and CD19-positive cells and provides a basis for future clinical studies.

A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7CD8 T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood. These data highlight SLAMF7 as a marker for suppressive CD8 Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients.

Finally, males had higher levels of negative for CD16, a key receptor mediating antibody-dependent cell cytotoxicity, which a major mechanism of anti-tumor efficacy by therapeutic antibodies such as elotuzumab.  In summary, we define major immune reconstitution patterns early after ASCT that can help guide the rational use of plasma cell directed monoclonal antibodies and checkpoint inhibitors early after ASCT. The presence of T cells at the 2 opposite ends of the T cell differentiation spectrum, in the group with the worst outcomes, suggests that the iTME of these patients is enriched in subsets unable to mediate effective clearance of malignant cells.

Finally, males had higher levels of negative for CD16, a key receptor mediating antibody-dependent cell cytotoxicity, which a major mechanism of anti-tumor efficacy by therapeutic antibodies such as elotuzumab.  In summary, we define major immune reconstitution patterns early after ASCT that can help guide the rational use of plasma cell directed monoclonal antibodies and checkpoint inhibitors early after ASCT. The presence of T cells at the 2 opposite ends of the T cell differentiation spectrum, in the group with the worst outcomes, suggests that the iTME of these patients is enriched in subsets unable to mediate effective clearance of malignant cells.

Finally, males had higher levels of negative for CD16, a key receptor mediating antibody-dependent cell cytotoxicity, which a major mechanism of anti-tumor efficacy by therapeutic antibodies such as elotuzumab.  In summary, we define major immune reconstitution patterns early after ASCT that can help guide the rational use of plasma cell directed monoclonal antibodies and checkpoint inhibitors early after ASCT. The presence of T cells at the 2 opposite ends of the T cell differentiation spectrum, in the group with the worst outcomes, suggests that the iTME of these patients is enriched in subsets unable to mediate effective clearance of malignant cells.

Finally, males had higher levels of negative for CD16, a key receptor mediating antibody-dependent cell cytotoxicity, which a major mechanism of anti-tumor efficacy by therapeutic antibodies such as elotuzumab.  In summary, we define major immune reconstitution patterns early after ASCT that can help guide the rational use of plasma cell directed monoclonal antibodies and checkpoint inhibitors early after ASCT. The presence of T cells at the 2 opposite ends of the T cell differentiation spectrum, in the group with the worst outcomes, suggests that the iTME of these patients is enriched in subsets unable to mediate effective clearance of malignant cells.

Since their approval, the anti-CD38 agent daratumumab, the anti-SLAMF7 agent elotuzumab, and most recently the anti-CD38 agent isatuximab have led to pivotal improvements in the treatment of double-refractory MM; currently, they are on their way to becoming integral parts in the up-front care of patients who have newly diagnosed MM, with daratumumab already approved in this setting. The accelerated approval of belantamab mafodotin represents an important milestone in antibody development; its ability to target B-cell maturation antigen (BCMA) in advanced disease is now established. Here, we present an overview of the currently available monoclonal antibody treatments in MM and discuss the clinical value, significant potential, and possible limitations of these immunotherapeutic approaches to driving deeper responses and achieving longer overall survival among patients with a challenging disease.

Costimulatory immune-checkpoint pathways by B7/CD28 were mainly activated, whereas those by PD-1/PD-L1 were inhibited. Our findings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.

The recent introduction of monoclonal antibodies (MoAbs), with several cellular targets, such as CD-38 (daratumumab and isatuximab) and SLAM F7 (elotuzumab), differently combined with other classes of agents, has significantly extended the outcomes of patients with multiple myeloma (MM) in different phases of the disease. In smoldering MM, MoAbs have been applied, either alone or in combination with other drugs, with the goal of delaying the progression to active MM and restoring the immune system. In this review, we will focus on the main results achieved so far and on the main on-going trials using MoAbs in SMM and NDTEMM.

Elotuzumab, the first in class targeting SLAMF7, in combination with lenalidomide and dexamethasone and daratumumab, directed against CD38, in combination with Rd and with bortezomib and dexamethasone (Vd), have been approved for the treatment of relapsed/refractory MM (RRMM) after they demonstrated excellent efficacy. More recently, another anti-CD38 MoAb named isatuximab was approved by FDA in combination with pomalidomide-dexamethasone (Pd) in the same setting...In this review we will describe the results of major clinical studies that have been conducted with elotuzumab, daratumumab and isatuximab in RRMM, focusing on phase III trials. Moreover, we will summarized the emerging MoAbs-based combinations in the RRMM landscape.

Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

Expression status of the CD5, CD20, CD37, CD38, CD40, CD150, and CD180 cell surface receptors could be used in prediction CLL B cells sensitivity to FLU, CP, BEN and FC ex vivo. Moreover, CD150 and CD180 receptors are involved in regulation of CLL B cells susceptibility to FLU and BEN. The CD150 and CD180 are positive regulators of CD20 expression that could make CD150CD180 CLL B cells more responsive to CD20-based immunotherapy.

The dose‑escalation utilizes a 3+3 design to identify the maximum tolerated dose of three doses of FT538 on Days 1, 8, and 15 as a monotherapy in r/r AML (Regimen A) and in combination with daratumumab (Regimen B) or elotuzumab (Regimen C) in r/r MM. The trial will test up to five FT538 dose levels ranging from 50 million to 1.5 billion cells, and up to 105 patients will be enrolled. The trial is expected to begin patient enrollment in 2020.

Combination of NKTR255 with current myeloma-targeting antibodies against CD38 and SLAMF7 (daratumumab and elotuzumab respectively) was effective against MM cells in vitro, with significant increase of antibody-dependent cellular cytotoxicity (ADCC) seen compared to single agents. Interestingly, the analysis of immune cells in blood, spleen and tumor tissue from the mice showed that daratumumab depleted, as expected, the total number of NK, CD8+ and CD4+ T cells (mostly at the expense of CD38+ cell subsets); but this depletion was prevented when daratumumab was employed in combination with NKTR-255. Taken together, our studies show that NKTR-255 restores NK cell activities in MM and provide evidences for clinical use of NKTR-255 as novel immunotherapeutic agent in MM alone or in combination with monoclonal antibodies.

STUDY DESIGN: Patients with RRMM who had received 2-4 prior regimens (including ≥ 2 consecutive cycles of daratumumab [DARA], an immunomodulatory agent, and a PI [individually or in combinations]) are randomized 2:1 to receive ide-cel or one of the following standard regimens based on the patient’s most recent regimen and investigator discretion: DARA + pomalidomide (POM) + dexamethasone (DEX; DPd), DARA + bortezomib + DEX (DVd), ixazomib + lenalidomide + DEX (IRd), carfilzomib + DEX (Kd), or elotuzumab + POM + DEX (EPd)...Ide-cel is manufactured following leukapheresis and then infused (at dose levels from 150 to 450 × 106, but targeting 450 × 106, CAR+ T cells) after 2 days of rest following lymphodepletion with 3 days of fludarabine 30 mg/m2 + cyclophosphamide 300 mg/m2...Immunogenicity and biomarkers are exploratory endpoints. KarMMa-3 is registered at ClinicalTrials.gov: NCT03651128.

Dara combinations with pomalidomide (pom), bortezomib (bor), thalidomide (thal), lenalidomide (len), or carfilzomib (car); and pom combinations that also included elotuzumab (elo) or Cytoxan (cytox) are noted in table 1...All pts received isa in combination with pom/dexamethasone (dex)...Further long term follow up will be needed to determine the length of response. Additional studies are planned to further evaluate this patient population.

Here, we evaluate the preclinical activity of IBER in combination with monoclonal antibodies (mAbs) and assess immune pharmacodynamic changes of IBER + daratumumab (DARA) among patients in the CC-220-MM-001 study...In co-culture assays, cell lines and immune cells were treated with clinically relevant concentrations of lenalidomide (LEN; 1 μM), pomalidomide (POM; 300 nM), and IBER (20 nM) alone, and in combination with DARA or elotuzumab (ELO). Clinical biomarker data were obtained from blood samples of patients enrolled in IBER + dexamethasone (DEX) and IBER + DARA + DEX cohorts of the CC-220-MM-001 study...Furthermore, immune changes observed by the addition of DARA to IBER + DEX were similar, suggesting IBER was the primary agent promoting immunomodulation in this triplet therapy. Together, these data support continued clinical development of IBER in combination with CD38- and SLAMF7-directed mAbs as well as other immune-directed therapies for the treatment of MM.

There are multiple advantages in expanding treatment options beyond autologous primary T and NK cells, including the use of induced pluripotent stem cells (iPSC) to derive effector cells that can be uniformly manufactured at scale from renewable starting cellular material and where precision genetic engineering can be achieved at the clonal level which can be applied sequentially in order to build multiple specificities and functional modalities...Utilizing hnCD16, BCMA-CAR was tested in combination with anti-CD38 (daratumumab), anti-SLAMF7 (elotuzumab), or anti-CD19, showing synergistic increase in tumor targeting through various tumor associated antigens (TAAs)...Combination with other monoclonal antibodies displayed a similar response demonstrating the unique ability of FT576 to be directed to target multiple TAAs. Together, these studies demonstrate the versatility of FT576 as a highly effective multi-antigen targeting and cost-effective off-the-shelf BCMA-CAR iNK cell product and supports the rational for a first-of-kind Phase I Study as a monotherapy or in combination with therapeutic mAbs targeted to MM-associated surface antigens, driving a path towards a curative therapeutic in MM.

FT538 is an investigational, first-of-kind, multiplexed engineered NK cell therapy generated from a clonal master engineered induced pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of off-the-shelf NK cells for broad patient access...Lympho-conditioning consisting of three consecutive days of fludarabine and cyclophosphamide will be administered prior to the first dose of FT538...Key exclusion criteria include active central nervous system disease, need for systemic immunosuppressive therapy, and prior allograft organ transplant. This trial is expected to begin patient enrollment in 2020.

In MAMMOTH, the individual CC regimens involving targeted therapies (carfilzomib, daratumumab, and elotuzumab) were associated with a median OS of between 8.3 and 12.7 months. Ide-cel provides clinically and statistically significant efficacy benefits over current CC, including combination regimens involving targeted agents.

However, B cell depletion with Rituximab, an anti-CD20 monoclonal antibody (mAb), failed to meet the primary endpoint in large clinical trials, possibly because antibody-producing plasma blasts/cells express low levels of CD20...Furthermore, commercially available mAb directed against SLAMF7 (Elotuzumab) and CD38 (Daratumumab) promote the immunogenicity of NK cells to specifically kill plasma blasts (Figure 3)... We showed that SLAMF7 and CD38 are aberrantly expressed or regulated on the surface of NK cells of SLE patients. The engagement of SLAMF7 or CD38 with mAb restores the function of SLE NK cells and promotes the killing of plasma blasts by NK cells. Our data indicates that targeting these receptors may represent future therapeutic options in SLE to eliminate autoantibody-producing cells.

CD319 is a suitable alternative to CD38 for identifying plasma cells. Our results showed that a panel used for monitoring multiple myeloma measurable residual disease could be modified by using CD319 alone or in combination with CD38 to detect PCs in daratumumab or elotuzumab treated patients.

Despite therapeutic progress in recent years with the introduction of targeted therapies (daratumumab, elotuzumab), multiple myeloma remains an incurable cancer. While the activity of 1100 kBq was highly toxic, the activity of 740 kBq offered the best efficacy with 65% of overall survival 150 days after the treatment with no evident sign of toxicity. This work demonstrates the pertinence of treating minimal residual disease of multiple myeloma with an anti-CD138 antibody coupled to astatine-211.

Recently, the introduction of new monoclonal antibodies against CD38 (Daratumumab and Isatuximab) and SLAM7 (Elotuzumab) has changed the therapeutic approach to MM, improving the response rate and the time to progression, both in newly diagnosed and refractory/relapsed patients. Experimental approaches targeting BCMA are currently being investigated and include antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs) and genetically engineered T-cells with chimeric antigen receptors (CAR). In this review we summarize the more recent findings about BCMA biologic rationale as a therapeutic target and report the updated results of preclinical and clinical studies focused on ADCs and bsAbs targeting BCMA.