Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients

Abstract

Background. New nontoxic targeted approaches are needed for patients with castrate resistant prostate cancer (CRPC). Our preclinical studies show that activated T cells (ATC) armed with anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) kill prostate cancer cells lines, induce a Th1 cytokine pattern upon engagement of tumor cells, prevent the development of prostate tumors, and retard tumor growth in immunodeficient mice. These studies provided strong rationale for our phase I dose-escalation pilot study to test ATC armed with Her2Bi (aATC) for safety in men with CRPC. Methods. Seven of 8 men with CRPC were evaluable after receiving two infusions per week for 4 weeks. The men received 2.5, 5 or 10 × 10(9) aATC per infusion with low dose interleukin-2 and granulocyte-macrophage colony stimulating factor. Results. There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores. Immune evaluations of peripheral blood mononuclear cells in 2 patients before and after immunotherapy showed increases in IFN-γ EliSpot responses and Th1 serum cytokines. Conclusions. These results provide a strong rationale for developing phase II trials to determine whether aATC are effective for treating CRPC.

Figures

Figure 1

The treatment schema. Her2Bi armed ATC (aATC) were administered twice weekly for four consecutive weeks. All patients received subcutaneous IL-2 (300,000 IU/m2/day) and GM-CSF (250 μg/m2/twice weekly), beginning 3 days before the first aATC infusion and ending 1 week after the last aATC infusion. Immune testing was performed at indicated time points.

Figure 2

(a) The transient decrease in PSA levels in two CRPC patients (60202 and 91760) who had minor responses. (b) A partial responder (60163) with the PSA levels declining by >50% within 6 months of completing therapy. (c) PostIT PSA levels in two nonresponding patients (FG00594 and FG00566) compared to their preIT baseline levels.

Figure 3

Number of IFN-γ producing cells when incubated overnight with prostate cancer cell line PC-3 in PBMC collected at baseline (preimmunotherapy [preIT]), during infusions (post inf#), and postimmunotherapy (1 week postimmunotherapy [1W postIT], 1 month postimmunotherapy [1 M postIT], and one year postimmunotherapy [1Y postIT]). (a) Increased number of IFN-γ producing cells during infusions and postIT time points in a partial responder (FG60163) when PBMC were incubated with prostate cancer specific PC-3 targets. (b) and (c) Enhanced IFN-γ responses in minor responders (FG60202 and FG91760).

Figure 4

Profile of serum cytokines. Analysis of sequential serum samples at baseline (preimmunotherapy [preIT]), during infusions (post inf#), and postimmunotherapy (1 week postimmunotherapy [1W postIT], 1 month postimmunotherapy [1 M postIT], and one year postimmunotherapy [1Y postIT]) shows increased levels of IL-2, IFN-γ, GM-CSF, and IL-10 and meanratio of Th1/Th2 = [IL-2+IFNγ]/[IL-4+IL-10] shows a dominant Th1 type response during aATC infusions in partial responder CRPC patient (FG60163). (b) and (c) Similar cytokine profiles and Th1 cytokine responses were seen in two minor responder CRPC patients (FG60202 and FG91760) during and after aATC infusions.