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Originally published as JCO Early Release 10.1200/JCO.2004.04.901 on June 1 2004 © 2004 American Society of Clinical Oncology.
Monoclonal Antibody Therapy for Prostate Cancer: Finally a Reality?University of California San Francisco Comprehensive Cancer Center, San Francisco, CA The development of monoclonal antibody therapy targeted at tumor antigens for the treatment of cancer has had some stunning successes: trastuzumab for HER2-positive breast cancer, rituximab for CD20-positive non-Hodgkin's lymphomas, cetuximab for EGFR-positive colorectal carcinoma, and gemtuzumab for CD33-positive myeloid malignancies. However, until now, prostate cancer has been notably absent from these successes. This is partly due to a lack of identified prostate- or prostate cancer–restricted antigens or cell surface molecules that can serve as targets. Two well-established antigens, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), have been well explored in a variety of immunotherapeutic strategies. Most investigators acknowledge, however, that targeting these particular antigens is problematic because of the large "sink" represented by large secreted pools of antigen. The work reported by Milowsky et al1 in this issue of the Journal of Clinical Oncology utilizing the monoclonal antibody J591 against prostate-specific membrane antigen (PSMA) is significant in this context. In many ways, PSMA represents an ideal target on prostate cancer cells. PSMA expression appears to correlate directly with aggressive biologic behavior, and has more robust expression in high-grade tumors compared with low-grade cancers, metastatic disease compared with localized disease, and hormone refractory compared with hormone sensitive disease. PSMA is not a secreted protein, but a cell-surface glycoprotein, making it a more attractive therapeutic target than PSA or PAP. Indeed, a radiolabeled murine antibody that binds to an intracellular epitope of PSMA is US Food and Drug Administration-approved as an imaging agent for soft tissue metastases in prostate cancer (Indium-111 capromab pendetide).2 While the ultimate clinical utility of this imaging agent is debatable, it nevertheless reflects the feasibilty of targeting PSMA. Just as PSMA appears to be an important target, J591 has several characteristics that set it apart as a promising agent. First, and perhaps most importantly, this antibody binds extracellular PSMA epitope(s), which allows enhanced targeting of prostate cancer cells, and potential for its internalization. Secondly, this murine antibody has been de-immunized by engineering it into a human immunoglobulin G1. This feature presumably avoids the issue of developing neutralizing human antimouse antibodies—and, as it turns out—human antihuman antibodies as well. Thus, J591 has the potential to both serve as a targeting agent, delivering toxic payloads, be they radioisotopes, toxins or chemotherapy, as well as to have direct cytotoxic effects by inducing antibody-dependent cellular cytotoxicity using naked antibody alone. Given an appropriate target, and a seemingly appropriate antibody, what then is the pathway to developing a clinically useful reagent? Previously, Bander et al3 undertook a phase I trial of J591 to define the dose of antibody to provide optimal tumor targeting. Armed with that information, this group now reports the results of a phase I trial with a therapeutic agent. J591 labeled with yttrium-90 (90Y) is a pure ß-emitter which has many attractive characteristics as a radiopharmaceutical. The authors also indicate that there is an ongoing trial evaluating J591 linked to a chemotherapeutic agent. While not specifically addressed, it would appear from the data presented that the promise of antibody-dependent cellular cytotoxicity made possible by the use of a naked antibody has not been borne out, or at least not robustly enough to warrant further testing. That is unfortunate, since the commercial development of radiopharmaceuticals has not been an easy task. This well-conducted study elucidates some of these challenges. The phase I nature of this trial resulted in the study of a heterogeneous group of patients. The failure to use PSA Consensus Criteria, nonstringent rules on LHRH-analogue and antiandrogen requirements, requirements for relatively uninvolved bone marrow, and variable prior chemotherapy all resulted in a cohort of patients that cannot necessarily be assumed to represent the average hormone refractory prostate cancer patient. To their credit, the authors undertook careful dosimetry, estimated on 111In-J591 imaging data (since yttrium-90 is not a gamma emitter). However, based on 111In-J591, 89% of patients with bone lesions and only 69% of patients with soft tissues were accurately targeted with the antibody. These observations raise important questions as this agent is further developed. Should this therapy be reserved only for 111In-J591–positive patients by radionuclide scans? Precedent certainly exists for the use of risk-adapted therapy, such as requiring immunohistochemical expression of a specific target for effective use of a monoclonal antibody (eg, trastuzumab in HER2-positive breast cancer). However, the practical implications (and limitations) of requiring imaging with a specific agent before therapy are clearly not trivial. The authors undertook a phase I dose escalation trial, in which the antibody dose was held constant, but the radiation dose was escalated. Therapy was well tolerated. Dose limiting events, primarily thrombocytopenia, occurred at a level of 20 mCi/m2. Somewhat surprisingly, dosimetry to marrow by 111In-J591 did not correlate with the degree of myelosuppression. Additionally, 11 of 29 patients had received prior chemotherapy, raising further questions. Did the extent of prior chemotherapy affect the marrow toxicity? In an era when taxane-based chemotherapy is rapidly being established as a standard of care for metastatic hormone refractory prostate cancer, how are these toxicity data to be interpreted? Similarly, only three patients underwent repetitive dosing. While it is encouraging to see that repetitive dosing can be accomplished, the only real conclusion is that multiple dosing requires further exploration. While this was a phase I trial, the preliminary antitumor activity is exciting: it points out that PSMA is a reasonable radioimmunotherapeutic target. Unfortunately, both responses that were observed occurred in a dose level higher than the maximum tolerated dose (MTD). This raises further questions: Is there a dose response relationship with this agent? If so, and responses were seen at a dose level retrospectively defined as "too toxic," is the therapeutic index for this agent too narrow? Clearly, additional studies are required, such as expanded phase II trials in which doses surrounding the MTD are explored, while accounting for type and extent of prior cytotoxic therapy. It is gratifying that a prostate cancer antigen can be targeted. However, we are a long way from using this agent routinely. Careful phase II work is required to define the proportion of patients that respond, and indeed the safe dose level, which was only approximated by the present trial. A more accurate assessment of the extent and duration of responses observed will need to be undertaken, and indirectly compared with the responses observed with taxane-based therapy, which is now considered first-line therapy for metastatic hormone refractory prostate cancer patients. Can we expect a response proportion of 40% to 60%, as we have come to expect from taxane-based therapy? If the response proportion is considerably lower than that observed with chemotherapy, then this radiopharmaceutical would best be developed as second-line therapy, after initial chemotherapy. Under these circumstances, the effect of prior chemotherapy on the MTD needs to be better understood, and a more detailed understanding of the natural history of these patients after first-line cytotoxic therapy will be necessary. Because of these limitations, it must be concluded that this agent is not yet ready to go into routine clinical use. Nevertheless, the study reported here by Milowsky et al1 is encouraging, and provides strong support for the principle that monoclonal antibody therapy for prostate cancer may finally become a reality. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Milowsky MI, Nanus DM, Kostakoglu L, et al: Phase I trial of yttrium-90–labeled antiprostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer. J Clin Oncol 22:2522-2531, 2004 2. Kahn D, Williams RD, Manyak MJ, et al: 111Indium-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy. The ProstaScint Study Group. J Urol 159:2041-2046, 1998[CrossRef][Medline] 3. Bander NH, Nanus D, Goldsmith S, et al: Phase I trial of humanized monoclonal antibody (mAb) to prostate specific membrane antigen/extracellular domain (PSMAext). Proc Am Soc Clin Oncol 19:477a, 2000 (abstr 1872)
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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