Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy

Abstract

Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.

Immunotherapy of recurrent B-cell malignancies after allo-SCT with Bi20 (FBTA05), a trifunctional anti-CD3 × anti-CD20 antibody and donor lymphocyte infusion

“…17 However, most patients ultimately relapse despite continued antibody treatment. 18 Mechanisms of resistance are not fully understood; some might be related to the tumor cells and some to host factors. Lymphoma cells may become resistant by decreased expression of CD20 antigen, or they may also activate antiapoptotic signal transduction pathways, which Immunotherapy of NHL with Bi20 and DLI R Buhmann et al renders these cells resistant to chemotherapy.…”

“…19,20 Host factors involve effector cells of antibody-dependent cellular cytotoxicity and the reticulo-endothelial system removing antibody-loaded cells. 18 These functions may be defective;…”

R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study

“…Several approaches to overcome this resistance are under evaluation, including drugs that interfere with intrinsic tumor-related resistance mechanisms and the development of a newer generation of monoclonal antibodies. 21,22 As far as concerns other relevant prognostic factors, response to R-ESHAP was one of the most important predictive factors for survival, with the best results for patients achieving complete remission ( Figure 1A and 1B). The most significant adverse prognostic factors for response in both the whole series and the R+ group were the presence of bulky disease, primary refractory disease, an aaIPI higher than 1 at the time of R-ESHAP, as well as the administration of fewer than three cycles of R-ESHAP.…”

IFNα kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model

“…In view of these specific indications, we have prepared a human IFN␣ kinoid exhibiting immunological characteristics similar to those described for huTNF␣ kinoid currently under clinical investigation and here for mIFN␣ kinoid. After its validation in humans, the vaccine could represent an anti-SLE medication in addition to current therapies and particularly an alternative in case of resistance to passive mAb therapy under clinical investigation (37). The kinoid vaccine provides substantial therapeutic advantages compared with passive immunization: (i) a generation of polyclonal autoAbs excludes the formation of Abs directed to themselves, the source of relapse; (ii) a serological monitoring of the frequency of vaccine boosters allows maintenance of an effective Ab threshold; and (iii) the low frequency of boosters fosters patient compliance.…”