This Phase 1 study investigated the safety and immunologic activity of lapuleucel-T, a novel, cell-based immunotherapy consisting of APCs activated with a recombinant fusion protein (BA7072) containing HER-2 sequences and designed to stimulate cellular immune responses against HER-2/neu.
In addition to passive immunotherapy such as trastuzumab, a number of previous studies of active immunologic therapies targeting HER-2/neu have been reported, including peptide approaches (20
) and dendritic cell based vaccines (24
). These approaches appear to be well-tolerated and induce robust immune responses. In addition, evidence of clinical activity has been reported in breast cancer in the adjuvant setting (21
). Possible advantages of the approach pursued here compared with peptide-based approaches include the potential to induce immune responses to multiple HER-2/neu epitopes, and the ability to include patients without regard to HLA haplotype. A previous study of an approach similar to lapuleucel-T, but targeting the tumor antigen prostatic acid phosphatase, has shown evidence of survival prolongation in men with advanced prostate cancer (9
In contrast to the toxicities associated with many other cancer treatments, lapuleucel-T therapy was generally well tolerated. The most common AEs reported in the study were fatigue and rigors. Most AEs were mild or moderate, were of short duration, and occurred soon after infusion of lapuleucel-T. The overall toxicity profile was generally similar to that reported for a previous study with lapuleucel-T in breast cancer (8
) and that of sipuleucel-T in men with advanced prostate cancer (9
). When AE incidence rates from this study were compared with those of the sipuleucel-T study, rigors and pyrexia appeared to occur more frequently in patients treated with sipuleucel-T than with lapuleucel-T (rigors 62.2% vs. 44.4%, and pyrexia 34.1% vs. 11.1%). Conversely, headache, nausea, and vomiting appeared to occur more frequently in patients treated with lapuleucel-T in this study compared with sipuleucel-T (headache 33.3% vs. 17.1%, nausea 33.3% vs. 14.6%, and vomiting 27.8% vs. 12.2%).
Immune responses to the immunizing antigen BA7072 were observed in this study. Responses to HER500 were also observed, but the magnitude of responses was lower.
The findings that proliferative immune responses were observed across all groups based on the level of HER2 expression, suggest that this form of active cellular immunotherapy may be applicable to patient populations where passive immunotherapeutic approaches targeting HER2 are not effective.
Immune responses were observed in patients receiving both configurations of lapuleucel-T (fresh lapuleucel-T followed by 2 infusions of cryopreserved lapuleucel-T, or 3 infusions of cryopreserved lapuleucel-T), which demonstrated the feasibility of this manufacturing approach. However, the administration of cryopreserved lapuleucel-T did not appear to result in as robust an immune response as that observed in the Park et al study (8
) which used only infusions of fresh lapuleucel-T. For example, the median proliferative response to BA7072 measured at Week 8 was 60.1 in the previous study, as compared with 15.4 in this study. The reason for the differences in immune responses is not known at this time. A possible reason for the difference could be the formulation of lapuleucel-T; the patients in this study received either 2 or 3 infusions of cryopreserved lapuleucel-T, whereas all infusions administered in the previous study were fresh lapuleucel-T.
An important aspect of this study was the inclusion of patients with HER-2 expressing malignancies other than breast cancer. Immune responses to lapuleucel-T were observed in patients with colorectal and ovarian cancers as well as in those with breast cancer.
A limitation of this study was the small number of patients enrolled. With the number of variables in the study design, including the concentrations of BA7072, the different product configurations (fresh and cryopreserved lapuleucel-T), and tumor types included, the study was not adequately powered to draw definitive conclusions regarding the comparative immunologic activity or efficacy of lapuleucel-T between groups.
Evidence of anticancer activity in this trial included short-term disease stabilization in 5 patients, and long-term disease stabilization lasting 48 weeks or more in 2 patients. The 2 patients with long-term disease stabilization both had breast cancer and were treated with 3 infusions of cryopreserved lapuleucel-T. One of these patients was also retreated with 3 infusions of lapuleucel-T approximately 1 year after initial treatment. This patient had stable disease at the time of the last follow-up visit, which occurred 72 weeks after initial treatment.
Breast, colorectal, and ovarian cancer comprise 3 of the 5 leading causes of death from cancer among women, and are expected to account for over 275,000 new cases in 2008 (25
). Given the number of patients affected by these diseases, and the toxicities associated with standard treatments, new treatment options are needed. We conclude that treatment with lapuleucel-T, a novel, cell-based immunotherapy, stimulated an immune response specific to the immunizing antigen and appeared to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu-expressing breast, ovarian, and colorectal cancer are warranted.
STATEMENT OF TRANSLATIONAL RELEVANCE
Lapuleucel-T (APC8024) is an investigational autologous active cellular immunotherapy designed to stimulate an immune response against tumor cells expressing the cancer antigen HER-2/neu. Such an active cellular immunotherapy approach may complement and/or synergize with passive immunotherapy approaches targeting HER-2/neu, such as trastuzumab. This study provides evidence that lapuleucel-T leads to an antigen-specific immune response in patients with breast, ovarian, and colorectal cancer. The therapy was well tolerated and was associated with prolonged disease stabilization in some patients. These findings, if confirmed in future clinical trials, may lead to new immunotherapy options for patients with HER-2/neu-positive malignancies.