In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA ...measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC).
Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. PSA measurements obtained before, and during, therapy were used. Data analysis using a two-phase mathematical equation yielded concomitant PSA growth and regression rate constants.
Growth rate constants (g) can be estimated while patients receive therapy and in such patients g is superior to PSA-DT in predicting OS. Incremental reductions in growth rate constants were recorded in successive trials with a 10-fold slower g in the most recent combination therapy trial (log g = 10(-3.17)) relative to single-agent thalidomide (log g = 10(-2.08)) more than a decade earlier. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration.
Incremental reductions in tumor growth rate constants suggest increased efficacy in successive chemotherapy trials. The derived growth rate constant correlates with survival, and may be used to assess efficacy. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. If validated as a surrogate for survival, growth rate constants would offer an important new efficacy endpoint for clinical trials.
The use of checkpoint inhibitor monoclonal antibodies (MAbs) has transformed the landscape of cancer immunotherapy. Consequently, human tumors can be characterized as either “hot” or “cold.” Hot ...tumors are defined by the presence of tumor infiltrating T-cell lymphocytes (TILs); melanoma is the prototype of a hot tumor. Studies have shown that the presence of TILs results in tumor cells expressing molecules, termed “checkpoints,” with the ability to anergize T cells. The clinical use of these checkpoint inhibitor MAbs has resulted in durable anti-tumor responses in approximately 50% of patients with melanoma and in 10%–15% of patients with some solid tumors such as lung cancer. The vast majority of solid tumors, that is, carcinomas of the breast, prostate, colon, and lung, as well as others, however, can be characterized as cold in that they do not respond to checkpoint inhibitor therapy. Preclinical studies and ongoing clinical studies are now revealing that a multi-modal approach to cancer immunotherapy can result in increased anti-tumor activity. This includes the use of agents designed to (a) activate the immune response with the use of vaccines, (b) potentiate the immune response with cytokines such as IL-15 and IL-12; these cytokines also have the potential to activate the innate immune system, for example, natural killer (NK) cells, (c) eliminate or reduce immunosuppressive entities such as TGF-beta, IL-8, and checkpoint molecules, and (d) modify the tumor phenotype to render tumor cells more susceptible to T-cell‒mediated attack. Recent preclinical and clinical studies have also shown that the use of bifunctional agents capable of bringing both immunostimulatory molecules as well as molecules to inhibit immunosuppressive entities to the tumor microenvironment results in enhanced anti-tumor activity.
The Society for Biological Therapy held a Workshop last fall devoted to immune monitoring for cancer immunotherapy trials. Participants included members of the academic and pharmaceutical communities ...as well as the National Cancer Institute and the Food and Drug Administration. Discussion focused on the relative merits and appropriate use of various immune monitoring tools. Six breakout groups dealt with assays of T-cell function, serologic and proliferation assays to assess B cell and T helper cell activity, and enzyme-linked immunospot assay, tetramer, cytokine flow cytometry, and reverse transcription polymerase chain reaction assays of T-cell immunity. General conclusions included: (1) future vaccine studies should be designed to determine whether T-cell dysfunction (tumor-specific and nonspecific) correlated with clinical outcome; (2) tetramer-based assays yield quantitative but not functional data (3) enzyme-linked immunospot assays have the lowest limit of detection (4) cytokine flow cytometry have a higher limit of detection than enzyme-linked immunospot assay, but offer the advantages of speed and the ability to identify subsets of reactive cells; (5) antibody tests are simple and accurate and should be incorporated to a greater extent in monitoring plans; (6) proliferation assays are imprecise and should not be emphasized in future studies; (7) the reverse transcription polymerase chain reaction assay is a promising research approach that is not ready for widespread application; and (8)there is a critical need to validate these assays as surrogates for vaccine potency and clinical effect. Current data and opinion support the use of a functional assay like the enzyme-linked immunospot assay or cytokine flow cytometry in combination with a quantitative assay like tetramers for immune monitoring. At present, assays appear to be most useful as measures of vaccine potency. Careful immune monitoring in association with larger scale clinical trials ultimately may enable the correlation of monitoring results with clinical benefit.
Objectives. Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment ...options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo.
Methods. A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction.
Results. Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline.
Conclusions. Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization.
Abstract
Purpose: The purpose of this study was to evaluate carbohydrate antigen array technology as a tool for identifying anti-glycan antibodies in human sera with potential as prognostic markers ...for prostate cancer.
Methods: A carbohydrate antigen array, or glycan array, containing 220 different glycans and glycoproteins was used to profile the anti-glycan antibody repertoire in sera from 29 prostate cancer patients. The Halabi nomogram was used to predict the survival for each patient. Relationships between antibody levels and the Halabi predicted survival were evaluated as a means to identify potential prognostic markers.
Results: A number of anti-glycan antibodies found in sera showed statistically significant correlations with the predicted survival for prostate cancer patients. Some examples include fucose-alpha (p = 0.009), fucosebeta (p = 0.023), Sialyl Lewis X (p = 0.014), and the Tn antigen (p = 0.022). For each of these antigens, higher antibody levels were associated with shorter predicted survival.
Conclusions: Anti-glycan antibodies have potential as prognostic markers for prostate cancer, and, based on the preliminary data, larger and more detailed studies are warranted.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):B43.
In a Phase II study, 14 patients with metastatic gastrointestinal cancer received the mAb D612 (40 mg/m2, days 4, 7, and 11) in combination with recombinant human monocyte colony-stimulating factor ...(rhM-CSF) 80 micrograms/kg/days 1-14. The combined treatment was well tolerated and resulted in characteristic biological activity associated with each of the agents. Thus, 10 of 14 patients experienced D612-associated secretory diarrhea, which responded to the prostaglandin inhibitor Indomethacin in 5 of 7 patients. rhM-CSF therapy was associated with peripheral monocytosis (peak absolute monocyte count, 1444 +/- 394/mm3) and thrombocytopenia (nadir count, 78 +/- 10/mm3). Monocyte surface marker analysis revealed a high baseline expression of CD16+ cells in our patient population with an additional increase with rhM-CSF therapy. We observed a correlation between the degree of thrombocytopenia and the pretreatment CD16+ monocyte count. Of the plasma cytokines assayed, serum Neopterin demonstrated the most consistent increase during rhM-CSF therapy. There was a significant difference in the half-life of the first and last dose of D612 (35.8 +/- 2 versus 27 +/- 2.9 h; P < 0.05). Eleven of fourteen patients developed low-moderate levels of anti-D612 antibody. Despite the observed biological activity of both rhM-CSF and D612 and the previously described in vitro synergy, no clinical antitumor responses were observed in this Phase II study.
The biodistribution and kinetics of 7 monoclonal antibodies (MAb) with known reactivity against CX-I tumor were examined over 21 days using a hand-held gamma-detecting probe (Neoprobe system). ...Twenty-eight irnmuno-deprived (athymic) nude mice implanted with human colon adenocarcinoma CX-1 xenografts were injected intraperitoneally with 50 µCi of125I-labeled antibodies (4 mice/antibody). Of the 7 monoclonal antibodies, 4 were anti-CEA (MA, MB, MC, and MD), 2 were anti-TAG 72 (B72.3 NCI and B72.3 fermented) and one was anti-colorectal cancer (17-1A). Daily probe counts were recorded in duplicate over the tumor site and the contralateral nontumor site (background), and tumor-to-background (Tu/Bkg) ratios were calculated. Animals were sacrificed on day 21, and blood, heart, liver, spleen, lungs, kidneys, intestine, muscle, and the tumor were removed for gamma well counting. All antibodies identified the tumor as early as 24 h postinjection and speciJic tumor localization improved over time. Patterns of prolonged tumor binding varied considerably from one antibody to another, although all but one (MB) showed continuously increasing TulBkg ratios. These data indicate progressive clearance of the antibodies from the background tissue and a persistence of labeled MAb activity in tumor resulting in improved tumor localizution with increasing postinjection time.
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