The introduction of proteasome inhibitors (PI) and immunomodulatory drugs (IMiD) has markedly increased the survival of multiple myeloma (MM) patients. Also, the unconjugated monoclonal antibodies (mAb) daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7) have revolutionized MM treatment given their clinical efficacy and safety, illustrating the potential of targeted immunotherapy as a powerful treatment strategy for MM. Nonetheless, most patients eventually develop PI-, IMiD-, and mAb-refractory disease because of the selection of resistant MM clones, which associates with a poor prognosis. Accordingly, these patients remain in urgent need of new therapies with novel mechanisms of action. In this respect, mAbs or mAb fragments can also be utilized as carriers of potent effector moieties to specifically target surface antigens on cells of interest. Such immunoconjugates have the potential to exert anti-MM activity in heavily pretreated patients due to their distinct and pleiotropic mechanisms of action. In addition, the fusion of highly cytotoxic compounds to mAbs decreases the off-target toxicity, thereby improving the therapeutic window. According to the effector moiety, immunoconjugates are classified into antibody-drug conjugates, immunotoxins, immunocytokines, or radioimmunoconjugates. This review will focus on the mechanisms of action, safety and efficacy of several promising immunoconjugates that are under investigation in preclinical and/or clinical MM studies. We will also include a discussion on combination therapy with immunoconjugates, resistance mechanisms, and future developments.

PURPOSE Circulating tumor DNA (ctDNA) has been used for disease monitoring in several types of cancer. The aim of our study was to investigate whether ctDNA can be used for response monitoring in neuroblastoma. METHODS One hundred forty-nine plasma samples from 56 patients were analyzed by quantitative polymerase chain reaction (qPCR) for total cell free DNA (cfDNA; albumin and β-actin) and ctDNA (hypermethylated RASSF1A). ctDNA results were compared with mRNA-based minimal residual disease (qPCR) in bone marrow (BM) and blood and clinical patient characteristics. RESULTS ctDNA was detected at diagnosis in all patients with high-risk and stage M neuroblastoma and in 3 of 7 patients with localized disease. The levels of ctDNA were highest at diagnosis, decreased during induction therapy, and not detected before or after autologous stem-cell transplantation. At relapse, the amount of ctDNA was comparable to levels at diagnosis. There was an association between ctDNA and blood or BM mRNA, with concordant results when tumor burden was high or no tumor was detected. The discrepancies indicated either low-level BM infiltration (ctDNA negative/mRNA positive) or primary tumor/soft tissue lesions with no BM involvement (ctDNA positive/mRNA negative). CONCLUSION ctDNA can be used for monitoring disease in patients with neuroblastoma. In high-risk patients and all patients with stage M at diagnosis, ctDNA is present. Our data indicate that at low tumor load, testing of both ctDNA and mRNA increases the sensitivity of molecular disease monitoring. It is likely that ctDNA can originate from both primary tumor and metastases and may be of special interest for disease monitoring in patients who experience relapse in other organs than BM.

Human immunodeficiency virus (HIV)-infected individuals successfully treated for tuberculosis (TB) remain at risk of recurrence of the disease, especially in high TB incidence settings. We performed a systematic review, investigating whether secondary preventive therapy (sPT) with anti-TB drugs (preventive therapy in former TB patients with treatment success) is an effective strategy to prevent recurrence of TB in this patient group. We searched the databases PubMed, Cochrane Library, EMBASE, Web of Science and Google Scholar using the keywords HIV-infections, HIV, human immunodeficiency virus, AIDS, isoniazid, isoniazid preventive therapy (IPT), tuberculosis, TB, recurrence and recurrent disease, resulting in 253 potential publications. We identified eight publications for full text assessment, after which four articles qualified for inclusion in this systematic review. The quality of the included articles was rated using the GRADE system. All but one study were rated as having a high quality. In all included studies, sPT significantly decreased the incidence of recurrent TB in HIV-infected individuals to a substantial degree in comparison to non-treatment or placebo. Relative reductions varied from 55.0% to 82.1%. These data showed that the use of sPT to prevent recurrent TB in HIV-infected individuals was highly beneficial. These findings need to be confirmed in prospective studies with an adequate assessment of the effect of antiretroviral therapy (ART) and the occurrence of drug resistance.

In the 2010s, immunotherapy revolutionized the treatment landscape of multiple myeloma. CD38-targeting antibodies were initially applied as monotherapy in end-stage patients, but are now also approved by EMA/FDA in combination with standards-of-care in newly diagnosed disease or in patients with early relapse. The approved SLAMF7-targeting antibody can also be successfully combined with lenalidomide or pomalidomide in relapsed/refractory myeloma. Although this has resulted in improved clinical outcomes, there remains a high unmet need in patients who become refractory to immunomodulatory drugs, proteasome inhibitors and CD38-targeting antibodies. Several new antibody formats, such as antibody–drug conjugates (e.g., belantamab mafodotin, which was approved in 2020 and targets BCMA) and T cell redirecting bispecific antibodies (e.g., teclistamab, talquetamab, cevostamab, AMG-420, and CC-93269) are active in these triple-class refractory patients. Based on their promising efficacy, it is expected that these new antibody formats will also be combined with other agents in earlier disease settings.

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16 + and granzyme B + NK cells, and higher frequency of TIM-3 + and HLA-DR + NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells.

Monoclonal antibodies (daratumumab, anti-CD38; elotuzumab, anti-SLAMF7) and BCMA-targeting T-cell redirecting therapies are highly effective in a large proportion of multiple myeloma (MM) patients. Nonetheless, age, prior (chemo)therapy, and the tumor-microenvironment may impair immune effector cell function and therefore significantly reduce the efficacy of these immunotherapies. Alternatively, an appealing strategy would be the use of targeted therapies, such as immunoconjugates, that directly kill the tumor cells. TAK-169, a novel CD38-specific immunotoxin armed with a deimmunized (DI) Shiga-like toxin A subunit (SLTA) payload, has been designed with this idea. TAK-169 induces irreversible ribosome inactivation of target cells with no dependency on immune effector cells. Prior studies showed that TAK-169 exerts potent cytotoxic activity against CD38-positive human MM cell lines in vitro and in xenograft mouse models (Willert et al. AACR 2019 Abstract 2384). Also, TAK-169 was well tolerated in mice and non-human primates (Willert et al. AACR 2019 Abstract 2384), and deimmunizing the SLTA molecule significantly reduced the in vivo immunogenicity of the payload (Willert et al. AACR 2015 Abstract 2477; Rajagopalan et al. AACR 2016 Abstract 595; Robinson et al. AACR 2017 Abstract 2695). We now assessed the preclinical activity of TAK-169 on a large panel of primary MM cells present in bone marrow (BM) samples from newly diagnosed (ND) (n=13), daratumumab-naive relapsed/refractory (RR) (n=11), and daratumumab-refractory (DR) RR (n=12) patients in flow cytometry-based cytotoxicity assays. In these samples, we also tested the impact of TAK-169 on non-malignant CD38-expressing hematopoietic cells, to gain insight into its on-target off-tumor effects. TAK-169 effectively lysed MM cells present in 36/36 BM samples in a dose-dependent fashion (Figure 1A; median maximal lysis 89%; range 45-100%; EC50: 36pM). Of note, MM cells from ND and daratumumab-naïve RR patients were equally sensitive to TAK-169-mediated lysis (Figure 1B and 1C; median maximal lysis 90%; range 76-100% vs. median maximal lysis 91%; range 76-98%). While MM cells from DR RR patients were also effectively killed, a fraction of these samples was less sensitive to TAK-169-mediated lysis (Figure 1B and 1C; median maximal lysis 66%, range 45-99%). We are currently exploring the impact of several patient and tumor characteristics, such as previous therapies and surface CD38 expression levels on MM cells, on the cytotoxic activity of TAK-169, and results will be reported. In the BM samples, the cytotoxic activity of TAK-169 was mainly restricted to MM cells - except for limited lysis of NK cells (median maximal lysis: 18%) and monocytes (median maximal lysis: 21%), no other non-malignant hematopoietic cells were lysed (Figure 1D), indicating a favorable therapeutic window generated by targeting CD38 with TAK-169. In conclusion, we show that TAK-169 induces powerful lysis of primary MM cells from both ND and RR MM patients, including those refractory to daratumumab. Our findings support the ongoing phase 1 clinical trial evaluating TAK-169 monotherapy in heavily pretreated MM (NCT04017130), and encourage preclinical evaluation of TAK-169 in other CD38-positive malignancies such as AML and T-ALL. Disclosures Higgins: Molecular Templates, Inc.: Current Employment, Other: Stockholder. Willert:Molecular Templates, Inc.: Current Employment, Other: Stockholder. Newcomb:Takeda Pharmaceuticals International: Current Employment, Other: Stockholder. Dash:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment, Other: Stockholder. Van De Donk:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mutis:Gadeta: Research Funding; Onkimmune: Research Funding; Takeda: Research Funding; Janssen Pharmaceuticals: Research Funding; Genmab: Research Funding.

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