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Acute Lymphoblastic Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Several promising investigational approaches involve the use of immuno-oncology products, ranging from the application of the next-generation allogenic and autologous CAR T-cell, second-generation BiTE antibodies and novel combinations of currently licensed drugs, such as the combination of the monoclonal antibody, rituximab, to various cytotoxic chemotherapy agents. Studies are also assessing the integration of epratuzumab and alemtuzumab. Targeted approaches have also expanded considerably with the expanding list of mutations and rearrangements that characterize ‘BCR-ABL1-like’ and other ‘novel’ ALL subtypes, which include ABL1, JAK2, JAK-STAT, CRLF2, EPOR and RAS, with ongoing studies assessing ABL1, JAK2 and mTOR inhibitors. The challenge here is that randomized studies will likely not be feasible, given the rarity of these diseases, and establishing clinical benefit will depend on the use of historical comparisons, as was the case in BCR-ABL1-positive ALL. Patients who express the cytokine receptor CRLF2, also noted in about 60% of DS-ALL, appear to benefit from JAK and mTOR inhibitors, in particular. Another drug of interest includes nelarabine (506U78), a prodrug that is rapidly demethylated to Ara-G, noted to have substantial clinical activity in T-ALL in first relapse and is now in clinical trials for newly diagnosed patients.
Specific Therapy for Lymphomas
Published in Tariq I Mughal, John M Goldman, Sabena T Mughal, Understanding Leukemias, Lymphomas, and Myelomas, 2017
Tariq I Mughal, John M Goldman, Sabena T Mughal
Other monoclonal antibodies include alemtuzumab (Campath), an anti CD52 agent, currently approved by FDA for the treatment of chronic lymphocytic leukemia (CLL). We have discussed this in chapter 8. Galiximab is an anti CD80 antibody which is being investigated in combination with rituximab, based on preclinical studies suggesting synergism. A recent study of this combination as initial therapy for indolent lymphomas suggests a response rate of 69%, including 41% complete responses. Further confirmation of this will clearly be of great interest. Galiximab appears to have minimal toxicity. Another antibody, epratuzumab, an anti CD22 agent, has resulted in 24% responses in follicular lymphoma and appears active in high-grade lymphomas also.
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Currently, a number of candidate drugs which target a relatively specific signalling abnormality or augments the immune response against CLL cells, are in clinical trials.165 Targeting BCL-2 selectively with ABT-199 and ABT-263 (Navitoclax) appears promising, given the founding role of BCL2 in the apoptotic process. Many efforts are also targeting PI3K-delta (PI3Kδ) and the lymph node and bone marrow microenvironment, which are considered to play a pivotal role in the leukaemogeneisis and lymphogenesis of B-cell malignancies. Candidate PI3Kδ inhibitor, such as idelalisib (IDELA) and SAR245408, have demonstrated efficacy in patients with relapsed/refractory CLL and other B-cell malignancies, when used as monotherapy or in combination with immunotherapy. Idelalisib, in combination with rituximab, has been noted to be effective when used as front-line treatment in all risk groups of CLL, including poor-risk.166 Ibrutinib, a potent BTK inhibitor and mediator of microenvironment is currently being considered for future first-line treatment of CLL.164 Other candidate investigational approaches include alisertib (MLN8237), an Aurora A kinase inhibitor, and several forms of immunotherapy. The immunotherapy efforts include several monoclonal antibodies, such as lumiliximab (anti-CD23), epratuzumab (anti-CD22), apolizumab (anti-HLA-DR), IDEC-114 (anti-CD80); and adoptive immunotherapy using CAR-T cells in conjunction with SCT (discussed in the ALL section).88,167
B cell depletion and inhibition in systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2023
Eugene Krustev, Ann E. Clarke, Megan R.W. Barber
Epratuzumab is a recombinant humanized anti-CD22 mAb that inhibits B cell function; however, when compared to anti-CD20 agents, there is a lesser degree of depletion [53]. The Study of Epratuzumab in Serologically Positive SLE Patients with Active Disease (EMBLEM) was a phase II placebo controlled RCT [54]. Improvements in SLE disease activity were measured by the British Isles Lupus Assessment Group-based Combined Lupus Assessment (BICLA; for each organ domain an improvement of all BILAG A scores to BILAG B or better and an improvement of all BILAG B scores to BILAG C or better, no new BILAG A, no more than one new BILAG B score, no worsening of SLEDAI score, ≤10% worsening in Physician Global Assessment [PGA], and no initiation of non-protocol treatments) [55]. At 12 weeks, there was a significantly greater proportion of patients treated with a cumulative epratuzumab dose of 2400 mg over 4 weeks who had a BICLA response when compared to placebo (placebo, 21.1%; epratuzumab combined 2400 mg 43.2%; odds ratio [OR] 2.9, 95% CI 1.2, 7.1). The most common adverse events were headaches, nausea, upper respiratory tract infections and dizziness [53]. Overall rates of adverse events, serious adverse events, infusion reactions and infections were similar between placebo and epratuzumab-treated patients [53].
Targeting primary Sjögren’s syndrome
Published in Modern Rheumatology, 2019
Toshio Odani, John A. Chiorini
CD22 is a type I transmembrane protein expressed on most mature B lymphocytes. CD22 is an inhibitory coreceptor of the B cell receptor (BCR). Epratuzumab does not act via B cell depletion but by binding to CD22 and enhancing CD22s inhibitory activity on the downstream signaling of BCR, thereby downregulating B cell activation [140]. Epratuzumab is the first humanized immunoglobulin (Ig)G1κ monoclonal antibody targeting CD22. The efficacy of epratuzumab in pSS was evaluated in a phase I/II open label study. Sixteen patients received 4 monthly infusions with epratuzumab, 53% achieved a clinical response. Statistically significant improvements were observed in fatigue, and patient and physician global assessments [141]. Epratuzumab showed effectiveness in a phase IIb trial in patients with moderate to severe active SLE [142]. In the post hoc analyses from the EMBODY phase III trials, treatment with epratuzumab in addition to standard therapies resulted in improved SLE specific clinical outcomes at week 48 compared with placebo in patients with a diagnosis of associated SS. No improvements in SLE specific clinical outcomes were observed in SLE patients without associated SS [143].
Epratuzumab for the treatment of systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2018
Epratuzumab is a humanized CD22 targeted IgG1 monoclonal antibody derived from the murine IG2a monoclonal antibody LL2, which binds to extracellular domain of CD22 [27]. Epratuzumab has low immunogenicity as only 5–10% of the molecule consists of murine sequence the rest being human [28]. Like many monoclonal antibodies it was first developed as a treatment for lymphoma [27]. Epratuzumab is given as an IV infusion typically with an infusion time between 30–60 min. Immunomedics Inc. developed epratuzumab originally for use in oncology [26,27] and licensed Union Chimique Belge (UCB) to develop epratuzumab for use in autoimmune diseases such as SLE.