Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis

Some minor histocompatibility antigens (mHags) are expressed exclusively on patient hematopoietic and malignant cells, and this unique set of antigens enables specific targeting of hematological malignancies after human histocompatability leucocyte antigen (HLA)–matched allogeneic stem cell transplantation (allo-SCT). We report the first hematopoietic mHag presented by HLA class II (HLA-DQA1*05/B1*02) molecules to CD4+ T cells. This antigen is encoded by a single-nucleotide polymorphism (SNP) in the B cell lineage-specific CD19 gene, which is an important target antigen for immunotherapy of most B cell malignancies. The CD19L-encoded antigen was identified using a novel and powerful genetic strategy in which zygosity-genotype correlation scanning was used as the key step for fine mapping the genetic locus defined by pairwise linkage analysis. This strategy was also applicable for genome-wide identification of a wide range of mHags. CD19L-specific CD4+ T cells provided antigen-specific help for maturation of dendritic cells and for expansion of CD8+ mHag-specific T cells. They also lysed CD19L-positive malignant cells, illustrating the potential therapeutic advantages of targeting this novel CD19L-derived HLA class II–restricted mHag. The currently available immunotherapy strategies enable the exploitation of these therapeutic effects within and beyond allo-SCT settings

Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma

The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumabrefractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR $15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255

The treatment of AL amyloidosis in the Netherlands in 2013

AL amyloidosis is the only form of amyloidosis caused by a small plasma cell clone in the bone marrow. The produced aberrant free light chain forms, together with serum amyloid P, deposits in several organs leading to organ dysfunction. Involvement of the heart is the most important prognostic factor. Treatment of systemic AL amyloidosis is based on treatments as used in multiple myeloma, however is much more complicated due to organ dysfunction and worse clinical condition of the patients. Aim of treatment is to achieve a complete haematological response. Organ responses can occur later on. High dose melphalan followed by stem cell transplantation is given to younger en fit patients. Older patients are treated with oral melphalan and dexamethasone. Bortezomib also seems to be well tolerated by patients and has good clinical efficacy. Several randomised phase III studies, such as the HOVON 104, have started to investigate superiority of treatment with proteasome inhibitors. Treatment of patients in clinical studies is highly recommended