anti-CD20 Antibody Research Articles

CNSC-60. SYNERGISTIC IMMUNOMODULATION THROUGH DUAL ANTIBODY THERAPY TARGETING CD47 AND CD24 FOR ENHANCED ANTITUMOR IMMUNITY IN GLIOBLASTOMA

Abstract Tumor cell phagocytosis by antigen-presenting cells (APCs) plays a pivotal role in fostering antitumor immunity. However, glioblastoma, known for its evasive strategies, exploits key phagocytosis checkpoints, including CD47, CD24, and beta-2-microglobulin. While mono-treatment targeting CD47 blockade has shown some antitumor responses in glioma, prolonged tumor-suppressing ability and significant extension of survival remain elusive. In this study, we combine anti-CD47 and anti-CD24 antibody treatments, unveiling a synergistic effect in promoting tumor cell phagocytosis. This enhanced phagocytosis profile triggers the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in APCs, thereby facilitating efficient T cell priming. This orchestrated interplay between innate and adaptive antitumor immunity not only attenuates glioblastoma growth and extends overall survival. These findings illuminate a promising avenue for harnessing phagocytosis modulation as a strategic approach to treat challenging tumors equipped with multiple immune checkpoints.

EXTH-40. IMMUNOPHENOTYPING OF RWTC-MBTA AUTOLOGOUS CANCER VACCINE IN PRECLINICAL GLIOBLASTOMA MODELS

Abstract Despite advances in immunotherapy, glioblastoma multiforme (GBM) remains challenging to treat due to its low inherent immunogenicity and a suppressive tumor microenvironment. Converting “cold” GBMs to “hot” tumors is crucial for effective immune activation and improved patient outcomes. We comprehensively characterized the rWTC-MBTA autologous cancer vaccine, consisting of Mannan-BAM-anchored irradiated whole tumor cells, Toll-like receptor ligands (LTA, Poly(I:C), R-848), and an anti-CD40 agonistic antibody, in preclinical GL261 and SB28 GBM models. A substantial number of vaccinated mice exhibited complete regression of GBM tumors in a T-cell-dependent manner, with no significant toxicity. Long-term tumor-specific immune memory was confirmed upon tumor rechallenge. In the vaccine-draining lymph nodes of the SB28 model, rWTC-MBTA vaccination triggered a major rise in cDC1 12 hours post-treatment, followed by an increase in cDC2, moDC, and pDC on Days 5 and 13. Enhanced cytotoxicity of CD4+ and CD8+ T cells in vaccinated mice was verified in co-culture with tumor cells. Comprehensive immunophenotyping in the GL261 and SB28 GBM microenvironments confirmed decreased regulatory T cells and increased CD4+ and CD8+ T cell infiltration in vaccinated mice. T-cell exhaustion analyses revealed an increase in the Tim3+CD8+ T cells. No significant differences were observed in the quantification of M-MDSC and PMN-MDSC between control and vaccinated mice, but PD-L1 expression significantly increased in M2 macrophages in vaccinated mice. Our findings demonstrate that rWTC-MBTA induces potent and long-term adaptive immune responses against GBM, warranting further investigation of combinations with other immunotherapies for enhanced efficacy.

IMMU-61. THE LAST OF US: A FUNGI BASED DENDRITIC CELL VACCINE

Abstract BACKGROUND Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults. The current standard treatment for newly diagnosed GBM involves maximal surgical resection followed by radiotherapy and temozolomide. Despite these interventions, the median overall survival for GBM patients remains approximately 15 months, highlighting the critical need for innovative therapeutic approaches. OBJECTIVE Our laboratory has previously developed a subcutaneous autologous tumor vaccine incorporating irradiated (IR) tumor cells with phagocytosis-stimulating ligands (Mannan-BAM), toll-like receptor (TLR) agonists, and an immunostimulant anti-CD40 antibody (collectively termed MBT). This combination has shown efficacy in mouse models of colon carcinoma, breast cancer, melanoma, and, more recently, gliomas. Our study aimed to create a dendritic cell (DC) vaccine using this strategy. METHODS To evaluate whether MBT could induce the maturation of DCs in vitro, we harvested BMDCs from mice and co-cultured them in the presence of MBT-tagged irradiated tumor cells. We then analyzed the maturation markers using flow cytometry and assessed cytokine production via ELISA. To test the efficacy of this approach in vivo, we utilized two different murine glioma models (SB28 and GL261). RESULTS Using flow cytometry, we observed a significant upregulation of important co-stimulatory molecules. Additionally, ELISA analysis demonstrated that MBT-treated DCs significantly increased the secretion of Type 1 cytokines while limiting the secretion of the regulatory cytokine IL-10. MBT-primed DCs combined with immune checkpoint inhibitor PD-1 increased mouse survival in a glioma model compared to WT mice. However, mice eventually succumbed to cerebral edema. Histology demonstrated significant treatment effects. CONCLUSION Our results demonstrate that MBT effectively matures DCs ex-vivo. Further research is required to immunophenotype the response to vaccination in glioma models and explore ways to overcome resistance.

Case report: The case report of ofatumumab, a fully human anti-CD20 monoclonal antibody, in the treatment of KLHL11 encephalitis

Case report: The case report of ofatumumab, a fully human anti-CD20 monoclonal antibody, in the treatment of KLHL11 encephalitis

The essential roles of memory B cells in the pathogenesis of systemic lupus erythematosus.

Emerging evidence indicates that memory B cells are dysfunctional in systemic lupus erythematosus (SLE). They are hyporesponsive to signalling through the B cell receptor (BCR) but retain responsiveness to Toll-like receptor (TLR) and type I interferon signalling, as well as to T cell-mediated activation via CD40-CD154. Chronic exposure to immune complexes of ribonucleoprotein (RNP)-specific autoantibodies and TLR-engaging or BCR-engaging cargo is likely to contribute to this partially anergic phenotype. TLR7 or TLR8 signalling and the resulting production of type I interferon, as well as the sustained activation by bystander T cells, fuel a positive feedforward loop in memory B cells that can evade negative selection and permit preferential expansion of anti-RNP autoantibodies. Clinical trials of autologous stem cell transplantation or of B cell-targeted monoclonal antibodies and chimeric antigen receptor (CAR) T cells have correlated replenishment of the memory B cell population with relapse of SLE. Moreover, the BCR hyporesponsiveness of memory B cells might explain the failure of non-depleting B cell-targeting approaches in SLE, including BTK inhibitors and anti-CD22 monoclonal antibodies. Thus, targeting of dysfunctional memory B cells might prove effective in SLE, while also avoiding the adverse events of broad-spectrum targeting of B celland plasma cell subsets that are not directly involved in disease pathogenesis.

CD38 as theranostic target in oncology.

CD38 is a multifunctional transmembrane glycoprotein found in multiple tissues and overexpressed in many cancer cells, notably in hematological malignancies such as leukemia and multiple myeloma (MM). Therefore, targeting CD38 remains an attractive strategy for cancer treatment in hematological malignancies as well as in solid tumors. It plays a critical role in the progression of these diseases through its ADP-ribosyl cyclase and cADPR-hydrolase activities. Its importance has led to the development of various anti-CD38 monoclonal antibodies (mAbs), including daratumumab and isatuximab, approved for MM treatment. These mAbs exert their anti-tumor effects through Fc-dependent immune mechanisms and immunomodulation, enhancing T-cell and NK-cell-mediated responses. However, resistance mechanisms arise during the treatment with daratumumab, creating the necessity for new therapies. This review explains current knowledge about the role of CD38 as a target in oncology and aims to delineate the use of single domain antibodies (sdAbs) as innovative theranostic tools in nuclear medicine. For diagnostic purposes, PET radionuclides like 68Ga, 64Cu, and SPECT radionuclides like 99mTc and 111In, are commonly used. Significant progress has been made in anti-CD38 radioligand therapy (RLT), with anti-CD38 antibodies providing insights into tumor biology and treatment efficacy. In terms of therapy, RLT is a promising approach that offers precise targeting of malignant cells while minimizing exposure to healthy tissue. This involves the use of radionuclides emitting α particles, like 225Ac, 212Pb or 211At, and β--particles like 90Y, 131I, or 177Lu, to exert cytotoxic effects. Derived from Camelidae heavy chain antibodies, sdAbs offer advantages over conventional mAbs such as small size, high stability, specificity, and ability to recognize hidden epitopes. CD38-specific sdAbs, such as sdAb 2F8, characterized by our laboratory, showing excellent tumor targeting and their engineered constructs, such as biparatopic antibodies and chimeric antibodies, represent a new generation of theranostic agents for diagnosis and treatment CD38-expressing malignancies.

Using Soluble CD38 to Overcome Daratumumab Interference in Pretransfusion Compatibility Testing

Background: CD38 is a protein highly expressed on myeloma (MM) cells that has been shown to be an effective target antigen for monoclonal antibody therapies, so treatment with anti-CD38 monoclonal antibodies is a first line therapy for patients with MM. Although CD38 is weaker expressed on erythocytes anti-CD38 binds to CD38 on reagent RBCs and cause panreactivity in vitro and subsequent false positive reactions in indirect antiglobulin tests (IAT), antibody detection (screening) tests, antibody identification panels, and anti-human globulin (AHG) crossmatches. These findings suggest that the soluble CD38 method could improve transfusion safety for patients receiving anti-CD38 therapy, particularly in urgent clinical settings This study aims to evaluate the effectiveness of a new soluble CD38-based method in mitigating Daratumumab interference during pretransfusion compatibility testing." Methods: We evaluated the Grifols sCD38 method in 20 patients and compared it with the DTT method Results: In our experience the sCD38 method reduced testing time from 150 to 50 minutes and demonstrated 100% efficacy, compared to 90% with DTT. The sCD38 effectively mitigated the interference caused by anti-CD38 antibodies in 10 (100% efficacy) of patient samples tested while DTT was successful in only 9/10 (90% efficacy); no interference was observed in patients presenting anti erythrocyte antibodies. Moreover, there was no negative influence on DTT sensitive blood group systems such as KEL upon sCD38 treatment. Conclusions: In our Laboratory, in the year 2023, we processed 129 patients treated with anti-CD38. Therefore the reduction from 150 to 50 minutes in the time needed to perform tests for mitigation of anti-CD38 interference appears to be relevant with a recovery of approximately 210 technical-hours per year. Another highly appreciated operational aspect was the possibility of treating the patient's plasma and perform tests using automatic instruments (Erytra Grifols) available in our laboratory. In the evaluation of this new method, we did not observe failures in the mitigation of anti-CD38 interference. Furthermore, the results obtained in the samples that presented allo or auto antibodies were not affected by the treatment with sCD38. In our experience Grifols sCD38 assay is straightforward and quick to perform ant it is superior to DTT treatment in the mitigation of anti-CD38 antibody interference in MM patients treated with Daratumumab.

Case report:Clinical manifestations and therapeutic options following rhTPO-induced neutralizing antibody production in a child with immune thrombocytopenia.

Recombinant human thrombopoietin (rhTPO) is commonly used to improve low platelet status in immune thrombocytopenia (ITP), as one protein product, even with a very low rate, there is still the possibility to produce neutralizing antibodies of thrombopoietin (TPO). We described a 7-year-old boy with ITP and normal TPO levels who had previously received rhTPO for 2 weeks but showed persistent thrombocytopenia and was misdiagnosed as acquired amegakaryocytic thrombocytopenia (AATP) and ineffectively treated with cyclosporine A (CsA) in combination with avatrombopag (AVA). As suspicious the TPO neutralizing antibody development as re-test of TPO level is 0, the CD20 + deletion antibody drug rituximab (RTX) was prescribed and received efficacy. rhTPO serves as one bio-protein drug and should be cautious with developing neutralizing antibodies if the drug effect is lost. The tests for antibody and/or TPO level should be done for the diagnosis, and the antibody eradication medication as an anti-CD20 antibody, RTX, should be prescribed to delete thes e neutralizing antibodies to recover the TPO level to reattain the response of ITP treatment.

The causal relationship between anti-CD20 antibodies and endometrial cancer: a Mendelian randomization study

PurposeTo determine the effects of anti-B cell surface marker CD20 antibody on the occurrence and progression of endometrial cancer to provide insights into clinical treatment in the future.MethodsWe performed a two-sample Mendelian randomization analysis (MR) to analyze the causal relationship between EC and immune cell markers. The genome-wide association study (GWAS) data of MS4A1 single nucleotide polymorphism encoding gene of CD20 were collected, and a drug target MR analysis was performed to detect the causal relationship between anti-CD20 antibody and the risk of EC. The risk of follicular lymphoma was used as a positive control, and EC was used as the outcome.ResultsEC exerted an effect on 28 immunophenotypes, predominantly on CD20. CD20 in immunoglobulin D+ CD38− B cells, memory B cells, and unsw memory B cells increased after EC onset. In addition, we detected one immunophenotype that exerted a dangerous effect on EC, i.e., CD3/TD CD4+ (mature stage of the T cell group). Simultaneously, CD20 could be used as both a risk factor and a protective factor for EC (P > 0.05). Anti-CD20 antibodies significantly reduced the risk of follicular lymphoma, including two GWAS pooled datasets. In addition, anti-CD20 antibodies exerted a protective effect on EC in two GWAS pooled datasets (P > 0.05).ConclusionOur study confirms the close relationship between CD20 and EC. Anti-CD20 antibodies may exert a protective effect on EC and reduce the risk of EC morbidity, providing a reference for future clinical diagnosis and treatment. However, further clinical verification of our results is warranted.

Early Rituximab versus Escalating Therapy in Neuromyelitis Optica: A Cost and Quality of Life Analysis

Introduction: Rituximab, an anti-CD20 monoclonal antibody, has shown effectiveness in reducing disease relapses and disability accrual through relapses in patients with neuromyelitis optica spectrum disorders (NMOSD). However, its higher cost compared to oral immunosuppressants raises questions about its cost-effectiveness, particularly in low and middle-income countries. This study aimed to compare the cost-effectiveness of early rituximab treatment versus escalation treatment in NMOSD patients. Methods: We conducted a retrospective study of NMOSD patients treated with rituximab in the first five years of disease at a hospital in São Paulo, Brazil, from 2015 to 2019. The Early Group consisted of NMOSD patients who received rituximab as a first-line treatment. The Escalating Therapy Group included patients who were prescribed rituximab after experiencing disease activity while on oral immunosuppressants, primarily azathioprine. An economic model based on Expanded Disability Status Score (EDSS) transitions was used to assess cost-effectiveness. Cost and utility data were derived from previous studies, and sensitivity analyses for different willingness to pay (WTP) thresholds and percentage of patients upscaling from oral immunossupressants to rituximab were performed. Results: Thirty NMOSD patients were included. In the Early Group, the proportion of patients reaching the highest EDSS states (6.5 or more) decreased over five years compared to baseline. In contrast, the Escalating Therapy Group experienced an increase in this proportion over the same period. Cost-effectiveness was achieved for willingness to pay (WTP) of €20-80,000 in our main analysis, sustained in our sensitivity analysis. Conclusion: Early treatment with rituximab has the potential to lower healthcare costs and enhance quality of life for NMOSD patients, supporting its early prescription for preventive treatment.

Venetoclax dose escalation rapidly activates a BAFF/BCL-2 survival axis in chronic lymphocytic leukemia

AbstractVenetoclax, a first-in-class BH3 mimetic drug that targets BCL-2, has improved the outcomes of patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. However, there are limited data on the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first 5 weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients based on proliferative, metabolic, and cell survival proteins. Venetoclax induced a significant reduction in all CLL subpopulations and caused rapid upregulation of the prosurvival BCL-2, BCL-XL, and mantle cell lymphoma-1 proteins in surviving cells, which had reduced sensitivity to the drug. In mouse models, the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted was recapitulated, and genetic models demonstrated that extensive apoptosis and access to the B cell cytokine, B cell activating factor (BAFF), were essential. Accordingly, in patients with CLL who were treated with venetoclax or the anti-CD20 antibody obinutuzumab there was marked elevation in BAFF and an increase in prosurvival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies through homeostatic factors and support cotargeting of cytokine signals to achieve deeper and more durable long-term responses.

Forimtamig, a novel GPRC5D targeting T cell bispecific antibody with 2+1 format for the treatment of multiple myeloma

Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. “Off-the-shelf” T-cell bispecific antibodies (TCBs) targeting BCMA and GPRC5D have demonstrated high objective response rates (ORR) in heavily pre-treated MM patients, however, primary resistance, short duration of response and relapse driven by antigen shift frequently occurs. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time to kill as many myeloma cells as possible. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format, using preclinical models of MM. Bivalent binding of forimtamig to the N-terminus of GPRC5D confers higher affinity as compared to classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care (SoC) agents including anti-CD38 antibodies, immunomodulatory drugs and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA-TCB and Cereblon E3 Ligase Modulatory Drugs (CELMoDs) was potent and prevented occurrence of GPRC5D-negative tumor relapse. Forimtamig is currently being evaluated in Phase 1 clinical trials in relapsed and refractory myeloma (RRMM) patients for monotherapy and in combination treatments. NCT04557150

Preclinical development of SGN-CD47M: Protease-activated antibody technology enables selective tumor targeting of the innate immune checkpoint receptor CD47.

CD47 is a cell surface glycoprotein that is expressed on normal human tissues and has a key role as a marker of self. Tumor cells have coopted CD47 overexpression to evade immune surveillance and thus blockade of CD47 is a highly active area of clinical exploration in oncology. However, clinical development of CD47-targeted agents has been complicated by its robust expression in normal tissues and the toxicities that arise from blocking this inhibitory signal. Further, pro-phagocytic signals are not uniformly expressed in tumors and antibody blockade alone is often not sufficient to drive antitumor activity. The inclusion of an IgG1 antibody backbone into therapeutic design has been shown to serve as an additional pro-phagocytic signal but also exacerbates toxicities in normal tissues. Therefore, a need persists for more selective therapeutic modalities targeting CD47. To address these challenges, we developed SGN-CD47M, a humanized anti-CD47 IgG1 monoclonal antibody linked to novel masking peptides through linkers designed to be cleaved by active proteases enriched in the tumor microenvironment. Masking technology has the potential to increase the amount of drug that reaches the tumor microenvironment, while concomitantly reducing systemic toxicities. We demonstrate that SGN-CD47M is well tolerated in cynomolgus monkeys and displays a 20-fold improvement in tolerability to hematologic toxicities when compared to the unmasked antibody. SGN-CD47M also displays preferential activation in the tumor microenvironment that leads to robust single-agent antitumor activity. For these reasons, SGN-CD47M may have enhanced antitumor activity and improved tolerability relative to existing therapies that target the CD47-SIRPα interaction.

COVID-19 in patients with chronic lymphocytic leukemia treated with venetoclax: what is the role of anti-CD20 antibody?

COVID-19 in patients with chronic lymphocytic leukemia treated with venetoclax: what is the role of anti-CD20 antibody?

Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation

AbstractTP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual Bruton tyrosine kinase and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multicenter, phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated patients with MCL with a TP53 mutation. Patients initially received 160 mg zanubrutinib twice daily and obinutuzumab. Obinutuzumab at a dose of 1000 mg was given on cycle 1 day 1, 8, and 15, and on day 1 of cycles 2 to 8. After 2 cycles, venetoclax was added with weekly dose ramp-up to 400 mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease (MRD) using an immunosequencing assay, treatment was discontinued. The primary end point was met if ≥11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with a TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of undetectable MRD (uMRD) at a sensitivity level of 1 × 10–5 and uMRD at a sensitivity level of 1 × 10–6 at cycle 13 was 95% (18/19) and 84% (16/19), respectively. With a median follow-up period of 28.2 months, the primary end point was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy end point in TP53-mutant MCL. These data support its use and further evaluation of the BOVen regimen in this high-risk population. This trial was registered at www.ClinicalTrials.gov as #NCT03824483.

Bispecific antibodies as bridging to BCMA CAR-T cell therapy for relapsed/refractory multiple myeloma.

Establishing a strategy for sequencing of T cell redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunological impact of bispecific T cell engaging antibodies (BsAb) as bridging therapy (BT) to subsequent BCMA-directed CAR-T cell therapies in 52 RRMM patients. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared to chemotherapy, anti-CD38 or anti-SLAMF7 antibody based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T cell expansion in patients receiving BsAb as BT. In vitro cytotoxicity of CAR-T cells was comparable amongst BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM.

Mice with Lymphatic Dysfunction Develop Pathogenic Lung Tertiary Lymphoid Organs that Model an Autoimmune Emphysema Phenotype of COPD.

We have previously shown that mice with loss of C-type lectin-like type II (CLEC2), which have lymphatic dysfunction due to the role of CLEC2 in platelets for maintaining separation between the venous and lymphatic system, develop lung tertiary lymphoid organ (TLO) formation and lung injury that resembles an emphysema phenotype of chronic obstructive pulmonary disease (COPD). We now sought to investigate whether and how TLOs in these mice may play a pathogenic role in lung injury that is relevant to human disease. We found that inhibiting TLO formation using an anti-CD20 antibody in CLEC2-deficient mice partially blocked the development of emphysema. TLOs in CLEC2-deficient mice were rich in plasma cells and were a source of a broad array of autoantibodies. Chronic cigarette smoke exposure increased the size and number of lung TLOs in CLEC2-deficient mice, and was associated with increased markers of antigen presentation and maturation, leading to increased autoantibody deposition. Using lung tissue from COPD patients, we found an increase in lymphatic markers in patients with an emphysema phenotype and autoreactive TLOs compared to COPD patients without emphysema that lack prominent TLOs. Taken together, these results demonstrate that emphysema in mice with lymphatic dysfunction can be partially rescued by blocking TLO formation, and that these TLOs are source of autoantibodies that are exacerbated by cigarette smoke. Our work suggests that lymphatic dysfunction in mice may recapitulate some aspects an autoimmune emphysema phenotype that is seen in a subset of patients with COPD.

Strengths and Weaknesses of Different Therapeutic Strategies for the Treatment of Patients with Multiple Myeloma Who Progress After the Frontline Use of Lenalidomide: A Narrative Review

Background/Objectives: Patients with multiple myeloma (MM) who relapse after exposure to lenalidomide in the context of their first-line therapy are becoming a growing and clinically relevant population. We performed a systematic review of available clinical trials evaluating the efficacy and safety of different therapeutic strategies for the treatment of patients with MM at first relapse after the frontline use of lenalidomide. Methods: Publications of interest were searched on the PubMed database. The following search terms were employed: relapsed multiple myeloma, refractory multiple myeloma, first relapse, second-line therapy, lenalidomide-refractory (Len-R) and lenalidomide-exposed (Len-Exp). Results: Overall, triplet regimens that included anti-CD38 antibodies, carfilzomib and dexamethasone achieved a more favorable PFS regardless of the number of prior therapies. Other trials also demonstrated a non-negligible benefit with combinations containing pomalidomide, particularly in early lines of therapy. However, the variable number of patients with Len-Exp/Len-R disease enrolled in these studies and the limited number of those analyzed after progression following frontline lenalidomide make it difficult to select an “optimal” choice for the treatment of patients with MM at first relapse. Promising results have been more recently obtained by using combo therapies, including belantamab mafodotin and, above all, immunotherapies with CAR-T cells, and ongoing clinical trials are exploring the role of bispecific antibodies and CELMoDs in this population of patients. Conclusions: In the absence of clear-cut data regarding the specific effects of available regimens on patients with MM who are refractory or have relapsed after first-line therapies including lenalidomide, novel approaches based on different types of immune strategies are expected to further improve the clinical outcome of these patients.

Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.

The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL. EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22+ Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m2 day 1, 0.5 mg/m2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS). Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10-4. Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10-4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study. Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

P4.11E.08 Integrated PK/PD Modeling for Uliledlimab, an Anti-CD73 Monoclonal Antibody, In Non-Small Cell Lung Cancer Patients

P4.11E.08 Integrated PK/PD Modeling for Uliledlimab, an Anti-CD73 Monoclonal Antibody, In Non-Small Cell Lung Cancer Patients