GM‐CSF as a systemic adjuvant in a phase II prostate cancer vaccine trial

Abstract

BACKGROUND. Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF; Leukine [sargramostim], Immunex Corp., Seattle, WA) was administered to a subgroup of 44 patients in a phase II clinical trial for prostate cancer using DC pulsed with HLA-A2-specific prostate-specific membrane antigen (PSMA) peptides. Our purpose was to determine if GM-CSF caused any enhancement of patients' immune responses, including enhancement of clinical response to the DC-peptide treatment. This report compares the clinical responses to DC-peptide infusions with and without systemic GM-CSF treatment. METHODS. GM-CSF was administered by subcutaneous injection at a dose of 75 g/m 2 /day for 7 days with each of six infusion cycles. Prefilled syringes were supplied to the patients for self-administration. RESULTS. One complete and 8 partial responders were identified among 44 patients who received GM-CSF, as compared to 2 complete and 17 partial responders among 51 patients who did not receive GM-CSF. For patients who received GM-CSF and were tested by delayedtype hypersensitivity (DTH) skin test, 3 cases of improved immune response were identified, compared to 5 cases of improvement in patients who did not receive GM-CSF. The main GM-CSF side effects reported were local reactions at the site of injection, fatigue, pain, and fever. Most reported side effects were of mild severity, with some cases of moderate severity leading to discontinuation of GM-CSF. CONCLUSIONS. Our results suggest GM-CSF as employed in this trial did not detectably enhance clinical response to DC-peptide infusions, or significantly enhance the measured immune response.

Therapeutic cancer vaccines: are we there yet?

“…Of greater concern, this trial also observed a trend toward worse overall survival in those patients who received GM‐CSF. These findings mirror results from earlier clinical studies where either reduced immunogenicity or a failure to augment immunogenicity was seen in vaccine regimens using GM‐CSF as an adjuvant compared to a control arm that did not receive the cytokine (70–73). The mechanism behind the reduced immune‐responsiveness observed in the presence of exogenous GM‐CSF remains to be completely determined.…”

Cryopreservation of adenovirus-transfected dendritic cells (DCs) for clinical use

“…Although satisfactory and clinically applicable cryopreservation methods for DCs have been described [18][19][20][21], methods to cryopreserve products transduced with Adv vectors have been little studied [22]. In most clinical trials reported to date, DCs were freshly prepared for each administration either from fresh blood [23][24][25][26][27], leukapheresis products [23,28,29], or from frozen aliquots of PBMCs obtained by leukapheresis [27].…”

Immune-based therapies for prostate cancer

“…Given all of these immunostimulatory properties, several groups have been investigating GM-CSF as a vaccine adjuvant [18][19][20]. Other groups have investigated administration of GM-CSF alone as a means of eliciting anti-tumor immunity.…”