Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs entered the clinic for treatment of several hematological cancers and solid tumors, and numerous more are under clinical investigation. The success of mAbs as cancer therapeutics lies in their ability to induce various cytotoxic machineries against specific targets. These cytotoxic machineries include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), which are all mediated via the fragment crystallizable (Fc) domain of mAbs. In this review article, we will outline the novel approaches of engineering these Fc domains of mAbs to enhance their Fc-effector function and thereby their anti-tumor potency, with specific focus to summarize their (pre-) clinical status for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM).

An activated immune system has been observed in patients with myelodysplastic syndrome but its exact contribution to disease development and control is not fully clarified. On the one hand an activated and skewed T-cell repertoire has been reported, but on the other hand, decreased natural killer cell function has been found. Immune activation could reflect undesired autoimmune reactions against normal hematopoietic precursor cells as well as effective immune-surveillance against dysplastic clones. We have investigated immune effector cells (lymphocyte subsets, lymphocyte activation markers, and natural killer cells) of 40 low and intermediate risk myelodysplastic syndrome patients and compared them to those of 10 age-matched healthy donors. Furthermore, we have analyzed the cytotoxic capacity of effector cells against autologous bone marrow hematopoietic precursor cells of 8 myelodysplastic syndrome patients and 2 healthy donors. In myelodysplastic syndrome patients, we have found an activated state of lymphocytes, determined by increased percentages of effector T cells with cytotoxic profile, more skewing of the T-cell receptor Vbeta (TCR-Vbeta) repertoire, and decreased frequencies of regulatory T cells, when compared to healthy donors. The percentage of natural killer cells did not differ between myelodysplastic syndrome patients and healthy donors, but natural killer cells of myelodysplastic syndrome patients expressed increased levels of granzyme B. Finally, we have demonstrated non-MHC restricted autologous cytotoxicity up to 90% against aberrant hematopoietic precursor cells, presumably mediated by natural killer cells. Our data point to a role for active immune-surveillance in myelodysplastic syndrome, as demonstrated by activated T cells and TCR-Vss skewing. Autologous cytotoxicity against hematopoietic precursor cells was natural killer cell dependent, which points to an additional role for the innate immune system in immune-surveillance of myelodysplastic syndrome patients.

Indoleamine 2,3-dioxygenase degrades the amino acid tryptophan which is essential for T cells. Tryptophan depletion causes T-cell cycle arrest and solid tumors that express high levels of indoleamine 2,3-dioxygenase can create immune suppression. Recently, blasts of patients with acute myeloid leukemia were shown to express indoleamine 2,3-dioxygenase. We determined INDO (encoding gene for indoleamine 2,3-dioxygenase) mRNA expression in leukemic blasts of 286 patients with acute myeloid leukemia by gene-expression profiling. Results were validated by quantitative polymerase chain reaction analysis in blasts of an independent cohort of 71 patients. High INDO expression was correlated to significantly shortened overall and relapse-free survival. Correlation of INDO expression to relevant known prognostic factors and survival identified high INDO expression as a strong negative independent predicting variable for overall and relapse-free survival. Inhibition of indoleamine 2,3-dioxygenase expressed by myeloid leukemic blasts may result in breaking immune tolerance and offers new therapeutic options for patients with acute myeloid leukemia.

Effective antitumor responses need the activation of CD4+ T cells. MHC class II antigen presentation requires the release of class II-associated invariant chain peptide (CLIP) from the antigen-binding site. In antigen-presenting cells, human leukocyte antigen DM (HLA-DM; abbreviated DM in this article) catalyzes CLIP dissociation. In B cells, HLA-DO (DO) down-modulates DM function. Cell surface CLIP:HLA-DR (DR) ratio correlates to DO:DM ratio and the efficacy of antigen presentation. We examined 111 blood and bone marrow samples of patients with newly diagnosed acute myeloid leukemia (AML) for the expression of CLIP, DR, DM, and DO by flow cytometry. Patients with DR+/CLIP− blasts had a significant longer disease-free survival than patients with DR+/CLIP+ blasts. DO, until now believed to be restricted to lymphoid cells, could be demonstrated at protein level as well as by reverse transcription-PCR. DO:DM ratio correlated to CLIP:DR ratio, suggesting that, unlike in other antigen-presenting cells of the nonlymphoid cell type, both DO and DM mediate regulation of CLIP expression in AML blasts. We hypothesize that DR+/CLIP− AML blasts are able to present leukemia-specific antigens to CD4+ T helper cells initiating an effective and long-lasting antitumor response resulting in a prolonged disease-free survival.

Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).

PURPOSE: Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS: We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS: A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION: Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.