A Pilot Trial of CTLA-4 Blockade with Human Anti-CTLA-4 in Patients with Hormone-Refractory Prostate Cancer

Abstract

Purpose: Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) augments and prolongsT-cell responses and is a strategy to elicit antitumor immunity. The objectives of this pilot study were to establish the pharmacokinetic and safety profile for a single dose of 3 mg/kg of the anti-CTLA-4 antibody Ipilimumab (MDX-010, BMS-734016) and to assess if this therapy resulted in prostate-specific antigen (PSA) modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in patients with hormone-refractory prostate cancer treated with Ipilimumab. Experimental Design: Patients with metastatic hormone-refractory prostate cancer received a single 3 mg/kg i.v. dose of Ipilimumab. Serologic measures of autoimmunity were obtained, and T-cell activation was evaluated by flow cytometry. Pharmacokinetic sampling of plasma for MDX-CTLA-4, PSA measurement, and diagnostic imaging were also undertaken. Results: Fourteen patients were treated: 12 patients received a single dose of Ipilimumab, and 2 patients were re-treated with a second dose upon PSA progression. Two patients showed PSA declines of z50%. Treatment was well tolerated with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritis requiring systemic corticosteroids. The mean F SD Ipilimumab terminal elimination half-life was 12.5 F 5.3 days. Conclusions: A single dose of 3 mg/kg Ipilimumab, an anti-CTLA-4 antibody, given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity. PSA-modulating effects observed warrant further investigation.

The Role of Regulatory T Cells in Mesothelioma

“…This "triple immunotherapy" looks particularly promising especially as all components of the "triple immunotherapy" have approved human equivalents or are undergoing clinical trials. Clinical trials have investigated TGF-β blockade [52] and denileukin diftitox (Ontak) to deplete Treg cells in a number of different cancers [53][54][55] while the use of anti-CTLA4 Ig (Ipilimumab, Bristol Myers Squibb) was approved for the treatment of melanoma based on a recent phase III clinical trial [56]. Although many of these Treg cell depletion strategies are showing promise, it is unlikely that they will be used as a single modality to treat an advanced stage mesothelioma patient.…”

B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome

“…A compelling precedent for abrogating inhibitory T cell signaling to enhance antitumor immunity has been established with the experience of CTLA-4 blockade (34-37). CTLA-4 blockade has also recently been investigated in patients with hormone-refractory prostate cancer (38). One distinct difference between CTLA-4 and other B7-CD28 members is that CTLA-4 ligand expression is limited to ''professional'' antigen presenting cells (dentritic cells, macrophages, etc.)…”

Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy

“…A number of these mAb have been shown to enhance immune responses when delivered systemically. 13,14 However, human studies have shown that such systemic delivery can lead to adverse effects [15][16][17][18][19][20] Thus, an advantage of our strategy is that by co-injecting antibody-secreting and antigen-presenting DC, secretion of antibody in the vicinity of DC presenting tumor antigen to T cells may skew the resulting enhanced immune response toward tumor-specific T cells while decreasing potential non-specific autoimmune reactions. We saw the enhancement of CTL responses only when the anti-GITR-secreting DC and antigen-presenting DC were co-injected at the same site and not when they were injected in opposite sites (Figure 4b).…”

“…Studies in mice have shown that these systemically delivered mAbs can produce the desired effect of enhancing protection against tumors and infectious diseases and many mAbs are currently in clinical trials with promising preliminary results. 13,14 However, immunomodulatory mAbs have been associated with adverse side-effects associated with their systemic administration, as observed in clinical trials with anti-CTLA-4 [15][16][17][18][19] and systemic and non-specific induction of inflammatory mediators as seen in the trial of the superagonistic mAb targeting CD28. 20 Another consideration in using these mAbs is that they are generally given in high doses (1-20 mg kg À1 ) over a period of time, resulting in expensive treatment costs.…”