P1, N=31, Completed, TeneoFour Inc. | Recruiting --> Completed | N=80 --> 31 | Trial completion date: Aug 2024 --> Jul 2023 | Trial primary completion date: Jan 2024 --> May 2023

P2, N=221, Active, not recruiting, GlaxoSmithKline | Trial completion date: Aug 2023 --> Jul 2024

CD38 knock-out CAR NK cells also demonstrated significantly higher levels of NK activation markers in co-cultures with both untreated and αCD38-treated MM cell lines. These NAM-cultured NK cells with the combined genetic approach of CD38 knockout and addition of CD38 CAR represent a promising immunotherapeutic tool to target MM.

Finally, we observed proliferation of CD34+CD38- progenitor cells, which might be relevant for lymphocyte proliferation and function, and additionally supporting potential modulating effect. Further analyses are being done to validate these findings.

ISB 1442 has 2 Fab domains binding to distinct CD38 epitopes that do not compete functionally with daratumumab. Treatment with ISB 1442 was well tolerated at the dose levels evaluated. The observed clinical CRS events were moderate and potentially related to macrophage activation following ISB 1442 administration. Updated clinical, biomarker and PK data will be presented for this ongoing study.

SAR442257 also induced CD25 and CD69 expression on normal T-cells suggesting efficient T-cell activation, (data not shown). Conclusion Altogether, this study shows that 1) most PTCL cells express at least CD28 or CD38, and 2) SAR442257 can efficiently kill malignant PTCL cells, while ensuring effective T-cell activation; In view of these results, clinical investigation of SAR442257 in PTCL is warranted.

After lymphatic preconditioning chemotherapy (program: fludarabine 30mg/m2/d and cyclophosphamide 300mg/m2/d, -5, -4, -3, for 3 consecutive days), all patients received a single dose of CART-BCMA at 2.5×106, 5×106 and 7.5×106 CAR-positive T cells/kg (subject body weight), according to the dose level in which they were enrolled...After the occurrence of CRS, all patients recovered without sequelae after supportive treatment, and 6 patients (40%) received tocilizumab (3 subjects received 2 doses, 3 subjects received 1 dose), 4 patients (26.7%) used glucocorticoids...Data from this phase 1 clinical study showed that CART-BCMA is well tolerated and highly efficacious in patients with RRMM. Patients with extramedullary plasmacytoma had the comparable response to those without extramedullary diseases. Notably, 12 patients (80%) patients elicted deeper response after 3 months of CART-BCMA infusion

CD38 upregulation was done by incubating with 10 or 25 nM panobinostat for 24 h and the apoptosis detection employed Annexin V and Propidium Iodide staining followed by flow cytometry analysis...Among them, we firstly prepared Epirubicin (EPI)-based pADCs, such as DARA-P-EPI, ISA-P-EPI and DRO-P-EPI (Fig.1A)...Notably, co-treatment of RPMI8226 cells with anti-CD38 and GDC0980, a PI3k/mTOR inhibitor, significantly improved cytotoxicity, suggesting DARA's potential for chemo sensitization (Fig.1G)... pADC's innovative design offers a high likelihood of successful clinical development and holds significant promise for MM therapy. Moreover, the unique mechanism provides potential to effectively overcome mAb and multiple drug resistance. Its facile nature allows for easy incorporation of multiple types of payloads into the ADC, making its synthesis highly scalable.

This bispecific antibody targets unique epitopes on CD38 and ICAM-1 on tumor cells with reduced red blood cell binding compared to the benchmark CD38 antibody daratumumab. Interestingly, combination of VP301 with the immunomodulatory drug, lenalidomide, led to synergistic anti-tumor growth activity in an in vivo efficacy study. In conclusion, the CD38 x ICAM-1 bispecific antibody VP301 demonstrated promising efficacy and specificity toward CD38+ and ICAM-1+ tumor cells and represents a novel approach for treating multiple myeloma and lymphoma.

Introduction: The implementation of CD38-targeting antibodies daratumumab and isatuximab into combination regimens including a proteasome inhibitor (PI) significantly improved outcome and prolonged survival of patients with multiple myeloma (MM)...In order to improve myeloma therapy, recently a phase II trial for RRMM patients was initiated combining the CD47 blocking antibody magrolimab with daratumumab or PIs (NCT04892446)...In responsive MM cell lines, ADCP mediated by CD38 antibodies in combination with the CD47 blocking antibody was slightly, but not significantly enhanced by pre-treatment with carfilzomib. Our findings demonstrate that blocking the CD47-SIRPa axis with a CD47 blocking antibody can improve ADCP of myeloma cells by therapeutic antibodies targeting CD38 and that PI treatment may enhance phagocytosis. Our findings demonstrate that blocking the CD47-SIRPa axis with a CD47 blocking antibody can improve ADCP of myeloma cells by therapeutic antibodies targeting CD38 and that PI treatment may enhance phagocytosis. Interestingly, there might be also MM cells with particular phenotypes rendering them resistant to phagocytosis. Further investigating these factors may help to identify MM patients that benefit from CD47 blockade.

CD19 CAR T-cells were constructed from PBMCs of rrLBCL patients obtained at the time of apheresis using a construct like axicabtagene ciloleucel (axi-cel). The tumor microenvironment of CAR T refractory rrLBCL is enriched in clonally expanded and terminally exhausted CD8 T-cells expressing CD38. The CD38/CD28xCD3 trispecific antibody SAR442257 boosted CAR T-cell activity through recognition of CD38 on the tumor, costimulation of CAR T-cells, and induced fratricide of CD38+ T-cells; resulting in superior tumor cell killing. In addition, SAR442257 allowed CD19 CAR T-cells to kill CD19- /CD38+ LBCL cells.

Belantamab Mafodotin (belamaf) is the first approved anti-BCMA ADC for the treatment of relapsed/refractory multiple myeloma (RRMM)...Three-phase III studies evaluate the safety and efficacy of belamaf in combination with pomalidomide (NCT04162210; DREAMM-3), daratumumab plus bortezomib (NCT04246047; DREAMM-7), or pomalidomide plus bortezomib (NCT04484623: DREAMM-8)...MEDI2228 has shown potent antitumor activity in preclinical models, including cell lines resistant to lenalidomide. Phase 1 data in heavily pretreated patients were encouraging.

A variety of cellular immunotherapies such as viral activated cytotoxic T-lymphocyte, chimeric antigen receptor (CAR) T-cells, NK and CAR NK-cells have been investigated and provide alternative options for CAYA patients with R/R NHL. Here, we provide an update and clinical practice guidance of utilizing these cellular and humoral immunotherapies in CAYA patients with R/R NHL.

Three ETBs (MT-0169, MT-5111, and MT-6402) are currently in clinical studies across different targets (CD38, HER2, PD-L1) and across hematologic malignancies, solid tumor, and immuno-oncology indications. ETBs can also deliver additional payloads to drive unique biology like the alteration of tumor immunophenotype. Here we describe three active clinical stage programs with encouraging safety and efficacy data that represent a transformation of the immunotoxin landscape into a more viable therapeutic approach to target validated as well as typically intractable clinical cancer targets.

Acute leukemia in Yemen was equally prevalent between adults and children with slightly more prevalent among males. Flow cytometry, even with a 3-colour strategy, is able to give useful diagnostic information about cell lineage of acute leukaemias. This has proven beneficial for patient management.

Since its approval by the US Food and Drug Administration in 2015, the monoclonal antibody specific for CD38, daratumumab, has been incorporated into both frontline and relapsed treatment regimens...Noteworthy naked monoclonal antibodies include isatuximab, another agent directed against CD38, and elotuzumab, an agent directed against SLAM family member 7...The first to market is belantamab mafodotin, which targets B-cell maturation antigen (BCMA) on malignant plasma cells and delivers a potent microtubule inhibitor, monomethyl auristatin F. Additionally, bispecific T-cell antibodies are in development that engage the immune system directly by simultaneously binding CD3 on T cells and a target epitope-such as BCMA, G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5)-on malignant cells. Currently, teclistamab, an anti-BCMA bispecific, is closest to approval for commercial use. In this review, we explore the evolving landscape of antibodies in the treatment of MM, including their role in frontline and relapse settings.

That in healthy tissues was under 27.7%ID/g. Considering the specific activity of 89Zr-anti-CD38 antibodies of 4.2 MBq/nmol, 89Zr-anti-CD38 antibodies accumulated in RPMI8226 tumors at approximately 730 fmol/mg.Conclusion We proposed a new imaging method, called WGI, which clearly visualized MM cells and was able to estimate the uptake values of 89Zr-anti-CD38 antibody binding to specific antigen in MM tumors.

7 cases with CMV infections were treated with ganciclovir (300mg bid intravenous for 2 weeks; 500mg tid po until CMV-DNA turned negative on 2 consecutive measurements) in combination with IVIG (400 mg/kg qd 5 days; 10 g biw maintenance until 1 week after DNA undetectable). In longitudinal analysis of the subpopulations of lymphocytes in PB, we observed NK cell and B cell depletion, and T cell expansion (especially CD8+T cell) after the treatment of Dara. Compared with patients without CMV and/or EBV infections during Dara-containing regimes, patients with CMV and/or EBV infections had significant lower absolute numbers of NK cells, total T cells, CD8+T cells at 1 month and absolute numbers of CD8+T cells at 2 months after the first Dara infusion.Conclusion : We observed a considerable risk of infections of EBV and/or CMV in the early stage of Dara treatment in patients with MM and speculated the potential involvements of NK cells depletion and CD8+T cells expansion in the occurrence of EBV and CMV infections.

Toxicities of interest include cytokine release syndrome and immune-effector cell-associated neurotoxicity. Exploratory analysis includes assessing the immune profile after pembrolizumab treatment, including changes in absolute lymphocyte count and lymphocyte subsets by flow-cytometry.This ongoing study (NCT05191472) is currently open and enrolling at University of California, San Francisco.

Significant differences were found between CD19+/ZAP-70+ and CD38 cases in patients with CLL-B with laboratory parameters associated with poor prognosis, showing the importance of using these cellular markers as independent prognostic indicators for these leukemias.

These data show the importance of immunophenotyping analysis by flow cytometry in patients with suspected ATLL.

Review of diagnostic genomic profile mid induction showed a BCR::ABL minor breakpoint fusion as well as CBF::GLIS fusion.The child began AML induction on COG AAML1831 trial randomized to the experimental arm with CPX-351 and gemtuzumab ozogamicin (GO). Due to lack of response to AML therapy at end of Induction (EOI) I, she was taken off protocol and started on modified ALL regimen for Induction II consisting of cytarabine, low dose weekly methotrexate and bimonthly peg-asparaginase with addition of an oral TKI, dasatinib...Given availability of FOLR1 directed ADC on single-patient compassionate use basis, patient received single agent STRO-001 on a bi-monthly basis...Long-term follow-up is required to assess durability of remission. Additional testing of this approach in a larger patient population is needed to determine the role of STRO-002 in this high-risk pediatric AML population.

"Based on our descriptive analysis, pts receiving cilta-cel achieved MRD negativity irrespective of their high-risk cytogenetics and ISS status, number of prior LOT and penta-drug refractoriness. While MRD negativity alone (<6 mo group) did not appear to provide PFS benefit when compared to MRD positive pts, the small number of pts in the MRD positive group prevents comparisons with those who achieved MRD negativity. Presence of extramedullary plasmacytoma at baseline, and time since diagnosis might be factors that impact achievement of sustained MRD negativity."

P2 | "Heavily pretreated MM patients with previous exposure to a non-cellular anti-BCMA therapy had favorable responses following cilta-cel. However, depth and DOR appear lower than that seen in anti-BCMA-naïve patients treated with cilta-cel (at 27.7 mos, median DOR was not reached in heavily pre-treated but anti-BCMA naïve CARTITUDE-1 patients). These results may inform tx plans, including sequencing and washout period between BCMA-targeting agents."

Liposomes were synthesized using the thin film hydration method followed by extrusion and functionalized them with the death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), immunoglobulin Fc-binding peptide (FCP, replicating the function of NK CD16 receptor) and the therapeutic antibody, anti-CD38 (daratumumab, Panel A) to target acute myeloid leukemia (AML)...Overall, we have developed an NK cell-mimic nanoparticle able to actively target AML based on AML surface marker expression without any detectable systematic toxicity. Importantly, due to the modular built of the NK.NPs, they can be functionalized by any therapeutic tumor-targeting antibody via the immunoglobulin-binding peptide (FCP), thus enabling selective targeting tumor cells based on expression of tumor-specific markers and enabling personalized therapy.

For example, the percentage of IFNy+ TNFa+ CAR iT cells increased by approximately 10-fold in a cytokine release assay when hnCD16+ CAR-MICA/B iT cells were combined with anti-CD38 antibody, daratumumab, to target Nalm6 cells...In an orthotopic ovarian tumor model where CAR iT cells demonstrate potent, but incomplete tumor control, in vivo activation of hnCD16 with therapeutic mAb enhanced tumor control and prevented tumor recrudescence. Together, these preliminary results demonstrate that specific arming of an off-the-shelf, allogeneic CAR iT cell product with a unique Fc receptor, hnCD16, enables a flexible and potent anti-tumor killing strategy to mitigate against tumor heterogeneity and to provide more durable and long-lasting responses in cancer patients.

Hence, an enhanced CD38 targeted therapy that unleashes the innate immune cell mediated tumor killing potential and overcomes daratumumab resistance mechanisms may present a unique opportunity to treat MM...Due to low-affinity binding to CD47, ISB 1442 engages CD47 efficiently only upon CD38 binding (avidity-induced binding), thereby reducing the potential for on-target, off-tumor effects, and it does not cause any detectable RBC depletion in vitro compared to magrolimab (Figure 2)...The study is currently open for enrollment. Clinicaltrials.gov identifier: NCT05427812.

At a median follow-up of 64.5 months, D-Rd improved efficacy versus Rd alone in subgroups of pts aged <75, <70, and ≥70 to <75 years. D-Rd demonstrated clinically meaningful benefit across all endpoints, including PFS, OS, ORR, and MRD negativity. These results, along with those presented previously (Usmani SZ, ASCO 2019), support the frontline use of DARA-based combination regimens in pts aged <75 years and ≥75 years with transplant-ineligible NDMM.

The non-targeting IgG1 isotype control mAb trastuzumab (TRA) did not bind C3d or enhance DARA-mediated killing. In summary, these results demonstrate that combination treatment of DARA with anti-C3d mAbs improves efficacy over single agent DARA leading to long-term survival in the MM.1R xenograft model. The combination of C3d targeting mAbs with DARA could improve clinical efficacy and overcome resistance to single agent therapy.

In this updated analysis of MAIA, the addition of DARA to Rd continued to demonstrate PFS and OS benefits in transplant-ineligible patients with NDMM after a median follow-up of >5 years. D-Rd also achieved a nearly 3-fold higher MRD-negativity rate and a ≥4-fold higher ≥12-month sustained MRD-negativity rate versus Rd alone. No new safety concerns were observed with longer follow-up.

Introduction Multiple myeloma (MM), the second most common blood cancer, is characterized by abnormal plasma cell growth in the bone marrow. Conclusion Our study proves SUMOylation inhibition potentiates Dara efficacy against multiple myeloma by increasing CD38 level in MM cells and activating immune cells including T, NK cells and monocytes in Type I IFN pathway dependent manner. Our work presents TAK-981 as an efficient combination to Dara therapy in MM treatment, with relevance to other mono antibody therapies for blood cancers and solid tumors.

In this updated analysis of ALCYONE, the addition of DARA to VMP continued to prolong OS versus VMP alone in transplant-ineligible patients with NDMM; median OS was reached in both arms for the first time after a median follow-up of >6 years. D-VMP also achieved a 4-fold higher MRD-negativity rate and a 5-fold higher ≥12-month sustained MRD-negativity rate versus VMP alone. No new safety concerns were observed with longer follow-up.

Thirty (68%) pts went on to receive further treatment (19 pts on BTK based regimens, 2 pts received venetoclax monotherapy, 5 pts received combined venetoclax and ibrutinib, 3 pts received chemoimmunotherapy, and 1 pt received obinutuzumab monotherapy). The PFS was similar to that of similarly designed trials with rituximab monotherapy and rituximab in combination with alemtuzumab, respectively. Further internal matched analysis is being conducted to compare time to second treatment.

Monoclonal antibodies such as mogamulizumab (anti-CCR4), alemtuzumab (anti-CD52), nivolumab (anti-PD1), pembrolizumab (anti-PD1), and the drug-antibody conjugate brentuximab vedotin (anti-CD30) have provided significant advances in the treatment of advanced/refractory CTCL, though patients still ultimately progress...This demonstrates that daratumumab shows efficacy as a single-agent in a systemic model of CD38+ CTCL when administered after disease onset... Overall, our studies demonstrate strong evidence for further investigation into the role of CD38 in the immunopathogenesis of CTCL and its value as a novel target for therapeutic intervention. Our data also provide preliminary evidence for the association between CD38 expression and disease progression in CTCL and suggest that the suppressive tumor microenvironment may contribute to disease progression.

These data provide a high-density roadmap of the distribution of known and novel AML-associated antigens together with the Fc receptor distribution and immune microenvironment in AML. The results motivated discovery of a novel antibody-therapeutic targeting aberrant cell-surface U5 snRNP200 and research into mechanisms for cell surface trafficking of U5 snRNP200.

This mechanism of action is differentiated from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. Treatment with ISB 1342 was well tolerated at the dose levels evaluated. The observed CRS events were moderate. Dose escalation continues with additional dose cohorts accruing.

Mononuclear cells (MNCs) were isolated, incubated for 48h with CD38 TriAb, nullCD38, nullCD28, daratumumab, isatuximab, or controls in triplicate wells for 48 h and MM cell survival analyzed by flow cytometry. The above data leads us to conclude that (1) CD38 TriAb is extremely potent, displaying EC50s in the picomolar range and (2) My-DST is able to measure CD38 TriAb efficacy ex vivo in primary samples through the patients' endogenous T cells to more closely recapitulate clinical administration. Further analysis is required to confirm that this data predicts a high response rate to CD38 TriAb in patients relapsed after anti-CD38 and anti-BCMA therapy. My-DST may be more broadly applicable to personalizing TCE treatment decisions, as individual patients may benefit from targeting one antigen over another in relapsed refractory multiple myeloma.

Outcomes are dismal when patients become refractory to bortezomib, lenalidomide, pomalidomide and daratumumab (quadri-refractory). Encouragingly, we observed that CCL27-based CAR-Ts with CCR10 knockout exhibited in vitro killing activity against MM.1S myeloma cells. In conclusion, our translational bioinformatics approach yielded novel antigen targets amenable for Chimeric Antigen Receptor-T (CAR-T) cell and HLA-independent T cell receptors (HIT receptors) approaches, potentially promising for the treatment of RRMM multiple myeloma patients.

Background: Current treatment options (cytarabine with anthracyclines) for patients with acute myeloid leukemia (AML) are often associated with severe and barely tolerable toxicities...An in vivo patient-derived AML PDX mouse model was treated with VIP943 (5 mg/kg IV every 7 days) or in combination with 5-azacytidine (2.5 mg/kg SC days 1-5 x 3) and venetoclax (50 mg/kg PO days 1-5 x 3)... VIP943 is a next-generation ADC with a differentiated safety profile from currently approved ADCs, including lack of in vitro cytokine release. In vitro and in vivo studies using patient-derived AML cells show VIP943 has favorable monotherapy and combination efficacy including targeting of leukemic stem cells, which drive relapse. These findings warrant evaluating VIP943 in clinical trials.

As dexamethasone (dex) is part of standard of care in MM, but could counteract the immune activation elicited by modakafusp, additional cohorts at 0.4 mg/kg Q3W and 1.5 mg/kg Q4W in combination with 40 mg dex QW were opened. Conclusions Modakafusp alfa has a novel mechanism of action, a manageable safety profile, and encouraging anti-myeloma activity at 1.5 mg/kg Q4W, independent of peripheral blood immune cell CD38 expression. A randomized phase 2 study to compare fixed-dose levels of 120 and 240 mg (equivalent to 1.5 and 3.0 mg/kg) Q4W and to define the single-agent dose with the optimal benefit/risk profile is currently enrolling.

With talquetamab treatment, patients in the 0.4 mg/kg SC QW cohort reported improvement in overall HRQoL and physical and role functioning and a decrease in pain and fatigue. These findings are consistent with the clinical benefits of talquetamab as demonstrated by the efficacy results from the MonumenTAL-1 study.