Exhaustion of Cytotoxic Effector Systems May Limit Monoclonal Antibody-Based Immunotherapy in Cancer Patients

Abstract

The CD20 mAb ofatumumab (OFA) induces complement-mediated lysis of B cells. In an investigator-initiated phase II trial of OFA plus chemotherapy for chronic lymphocytic leukemia (CLL), OFA treatment promoted partial CLL B cell depletion that coincided with reduced complement titers. Remaining CLL B cells circulated with bound OFA and covalently bound complement breakdown product C3d, indicative of ongoing complement activation. Presumably, neither complement- nor effector cell-based mechanisms were sufficiently robust to clear these remaining B cells. Instead, almost all of the bound OFA and CD20 was removed from the cells, in accordance with previous clinical studies that demonstrated comparable loss of CD20 from B cells after treatment of CLL patients with rituximab. In vitro experiments with OFA and rituximab addressing these observations suggest that host effector mechanisms that support mAb-mediated lysis and tumor cell clearance are finite, and they can be saturated or exhausted at high B cell burdens, particularly at high mAb concentrations. Interestingly, only a fraction of available complement was required to kill cells with CD20 mAbs, and killing could be tuned by titrating the mAb concentration. Consequently, maximal B cell killing of an initial and secondary B cell challenge was achieved with intermediate mAb concentrations, whereas high concentrations promoted lower overall killing. Therefore, mAb therapies that rely substantially on effector mechanisms subject to exhaustion, including complement, may benefit from lower, more frequent dosing schemes optimized to sustain and maximize killing by cytotoxic immune effector systems.

Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells

“…As a loading control, samples were stained for β-actin. 35 While fH has been described as contributing to the protection of several solid tumors and tumor cell lines, [19][20][21][36][37][38][39] its involvement in the resistance of CLL cells to CDC has not yet been reported. By contrast, the role of CD55 and CD59 in the context of CLL has been investigated in more detail.…”

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

“…67 That cytotoxic effector mechanisms can be reduced due to complement consumption further supports the role of complement in mAb therapy. 68,69 The use of fresh-frozen plasma as a source of complement in combination with rituximab has been evaluated in refractory CLL patients and resulted in a remarkable clinical response. 70,71 Other data, however, suggest that complement can be detrimental in mAb therapy.…”

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

“…12,100 The immune effectors may also become partly or temporarily depleted after RTX administration due to their consumption in vivo. 101 For example, after i.v. administration of RTX, complement is activated very quickly and some limiting components of the system, such as the C2 fragment, are exhausted after repeated administrations.…”