Ronald D. Alvarez

Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity

Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibition of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, virtually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and interferon (IFN)-γ. T cells conditioned with the B7-H1–blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic–severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one approach for cancer immunotherapy.

Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study.

PURPOSE To assess progression-free survival (PFS) and overall survival (OS) in patients with suboptimally debulked epithelial ovarian cancer receiving cisplatin (100 mg/m(2)) or 24-hour infusion paclitaxel (200 mg/m(2)) or the combination of paclitaxel (135 mg/m(2)) followed by cisplatin (75 mg/m(2)). PATIENTS AND METHODS After stratification for disease measurability, patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined. RESULTS Six hundred fourteen of 648 patients who entered onto the trial were eligible. Monotherapies were discontinued more frequently (cisplatin because of toxicity or patient refusal [17%], and paclitaxel because of progression [20%]) compared with the combination therapy (7% and 6%, respectively). Neutropenia, fever, and alopecia were more severe with paclitaxel-containing regimens; whereas anemia, thrombocytopenia, neurotoxicity, nephrotoxicity, and gastrointestinal toxicity were more severe with cisplatin-containing regimens. The CR/PR rates on paclitaxel monotherapy were significantly lower compared with the cisplatin regimens (42% v 67%, respectively; P <.001). The relative hazard (RH) of first progression or death was significantly greater among those randomized to paclitaxel (RH = 1.41; 95% confidence interval [CI], 1.15 to 1.73; P <.001) when compared with cisplatin; however, RH did not differ significantly between the two cisplatin regimens (RH = 1.06; 95% CI, 0.895 to 1.30). Relative to cisplatin, the death rate on paclitaxel was 15% greater (RH = 1.15; 95% CI, 0. 929 to 1.42), and the death rate on the combination treatment was 1% less (RH = 0.99; 95% CI, 0.795 to 1.23). These differences among treatment groups were not statistically significant (P =.31). CONCLUSION Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms, and the combination therapy had a better toxicity profile. Therefore, the combination of cisplatin and paclitaxel remains the preferred initial treatment option.

Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma : A dose-response study by the gynecologic oncology group

PURPOSE Progestins have definite activity against advanced or recurrent endometrial carcinoma. Both parenteral and oral progestins yield similar serum levels and response rates, which range from 18% to 34%. The one major study that used oral medroxyprogesterone acetate (MPA) noted a response rate at the lower end of the range (18%) and much poorer progression-free and overall survival times (4 and 10.5 months, respectively) than previously reported. The present study sought to confirm this earlier study of oral MPA, to assess the importance of prognostic factors such as histologic grade and receptor levels, and to determine whether a higher dose of MPA would yield a higher response rate. PATIENTS AND METHODS Two hundred ninety-nine eligible women with advanced or recurrent endometrial carcinoma were randomized to receive oral MPA either 200 mg/d or 1, 000 mg/d until unacceptable toxicity intervened or their disease progressed. RESULTS Among 145 patients receiving the low-dose regimen, there were 25 complete (17%) and 11 partial (8%) responses for an overall response rate of 25%. The 154 patients receiving the high-dose regimen experienced 14 (9%) complete and 10 (6%) partial responses for an overall response rate of 15%. Median durations of progression-free survival were 3.2 months and 2.5 months for the low-dose and high-dose regimens, respectively. Median survival durations were 11.1 months and 7.0 months, respectively. The adjusted relative odds of responding to the high-dose regimen compared with the low-dose regimen was 0.61 (90% confidence interval, 0.36 to 1.04). Prognostic factors having a significant impact on the probability of response included initial performance status, age, histologic grade, and progesterone receptor concentration. Compliance with oral therapy was documented with serum levels 1 month after starting therapy, when possible. MPA levels were commensurate with the assigned dose and schedule. CONCLUSION Oral MPA is active against endometrial carcinoma. Response to progestin therapy is more frequent among patients with a well-differentiated histology and positive progesterone receptor status. This study provides no evidence to support the use of MPA 1,000 mg/d orally instead of MPA 200 mg/d orally. In fact, the trends suggest the opposite. The use of oral MPA 200 mg/d is a reasonable initial approach to the treatment of advanced or recurrent endometrial carcinoma, particularly those lesions that are well-differentiated and/or progesterone receptor-positive (> 50 fmol/mg cytosol protein). Patients with poorly differentiated and/or progesterone receptor levels less than 50 fmol/mg cytosol protein had only an 8% to 9% response rate.

Stem Cell Pathways Contribute to Clinical Chemoresistance in Ovarian Cancer

Purpose: Within heterogeneous tumors, subpopulations often labeled cancer stem cells (CSC) have been identified that have enhanced tumorigenicity and chemoresistance in ex vivo models. However, whether these populations are more capable of surviving chemotherapy in de novo tumors is unknown. Experimental Design: We examined 45 matched primary/recurrent tumor pairs of high-grade ovarian adenocarcinomas for expression of CSC markers ALDH1A1, CD44, and CD133 using immunohistochemistry. Tumors collected immediately after completion of primary therapy were then laser capture microdissected and subjected to a quantitative PCR array examining stem cell biology pathways (Hedgehog, Notch, TGF-β, and Wnt). Select genes of interest were validated as important targets using siRNA-mediated downregulation. Results: Primary samples were composed of low densities of ALDH1A1, CD44, and CD133. Tumors collected immediately after primary therapy were more densely composed of each marker, whereas samples collected at first recurrence, before initiating secondary therapy, were composed of similar percentages of each marker as their primary tumor. In tumors collected from recurrent platinum-resistant patients, only CD133 was significantly increased. Of stem cell pathway members examined, 14% were significantly overexpressed in recurrent compared with matched primary tumors. Knockdown of genes of interest, including endoglin/CD105 and the hedgehog mediators Gli1 and Gli2, led to decreased ovarian cancer cell viability, with Gli2 showing a novel contribution to cisplatin resistance. Conclusions: These data indicate that ovarian tumors are enriched with CSCs and stem cell pathway mediators, especially at the completion of primary therapy. This suggests that stem cell subpopulations contribute to tumor chemoresistance and ultimately recurrent disease. Clin Cancer Res; 18(3); 869–81. ©2011 AACR.

Identification of prognostic factors and risk groups in patients found to have nodal metastasis at the time of radical hysterectomy for early-stage squamous carcinoma of the cervix☆

In a retrospective study conducted at the University of Alabama at Birmingham, the University of Michigan, and the Mayo Clinic, 185 patients with previously untreated FIGO stage IB and IIA squamous cell carcinoma of the cervix were found to have nodal metastasis at the time of radical hysterectomy and pelvic lymphadenectomy. Of these patients, 103 received adjuvant pelvic irradiation. Cancer recurred in 76 patients; the median time to recurrence was 3.1 years. The prognostic significance of patient age, clinical stage, lesion diameter, number and location of nodal metastases, and use of adjuvant radiation therapy was determined by multivariate analysis. Only patient age (P = 0.0006), lesion diameter (P less than 0.0001), and number of nodal metastases (P = 0.0004) were noted to be significant factors in determining overall survival. Rates of recurrence were also related to these factors. Employment of these significant variables led to identification of four risk groups. In general, patients with small cervical lesions (diameter less than 1 cm) and no more than two nodes with metastases fell into the low-risk category; those patients with large cervical lesions (diameter greater than 4 cm) and more than two involved nodes fell into the high-risk category. All other patients were categorized into intermediate-risk groups. Ten-year survival was 92% in the low-risk group (n = 13), 70% in the low-intermediate-risk group (n = 66), 56% in the high-intermediate-risk group (n = 66), and 13% in the high-risk group (n = 20). This risk group classification identifies subgroups of early-stage cervical carcinoma patients found to have nodal metastasis at the time of radical hysterectomy that warrant appropriately selected adjuvant therapy.

Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus

Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie-adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Delta24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Delta24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Delta24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Delta24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.

Value of adjuvant whole-pelvis irradiation after Wertheim hysterectomy for early-stage squamous carcinoma of the cervix with pelvic nodal metastasis: A matched-control study☆

In a retrospective study, 185 patients with previously untreated stage IB or IIA (International Federation of Gynecology and Obstetrics) squamous cell carcinoma of the cervix were found to have pelvic nodal metastasis at the time of Wertheim hysterectomy and bilateral pelvic lymphadenectomy. Of these patients, 103 received adjuvant whole-pelvis irradiation and 82 received no adjuvant therapy. Median dose of pelvic irradiation was 5000 cGy. Among the irradiated patients, in 75% the dose was 5000 cGy or greater. Matching irradiated and nonirradiated patients according to stage, tumor size, and number and location of positive nodes yielded 60 pairs. Mean length of follow-up was 3.9 years for the 60 irradiated patients and 5.8 years for the non-irradiated patients. Kaplan-Meier overall and cancer-specific survival estimates for the two groups were not significantly different (P greater than 0.30). During the follow-up period, 21 surgery-only patients and 22 patients treated with adjuvant radiotherapy had recurrence, but adjuvant radiotherapy decreased the proportion of recurrences occurring in the pelvis alone--27% compared with 67% in the surgery-only group (P = 0.01).

Targeted tumor killing via an intracellular antibody against erbB-2.

Specific killing of erbB-2-overexpressing tumor cells can be achieved using expression of an intracellular antibody directed against the erbB-2 oncoprotein. We have developed a strategy using a recombinant adenovirus encoding an anti-erbB-2 single chain antibody to achieve targeted tumor cell killing in vivo and can show significantly prolonged survival of animals carrying a human ovarian carcinoma tumor burden within their peritoneal cavities. This strategy of gene therapy for ovarian carcinoma offers the potential to achieve highly specific, targeted killing of human tumor cells and thus establishes the rationale to undertake human clinical trials on this basis.

Pretreatment with cisplatin enhances E7-specific CD8+ T-Cell-mediated antitumor immunity induced by DNA vaccination.

Purpose: Because the combination of multiple modalities for cancer treatment is more likely to generate more potent therapeutic effects for the control of cancer, we have explored the combination of chemotherapy using cisplatin, which is routinely used in chemotherapy for advanced cervical cancer, with immunotherapy using DNA vaccines encoding calreticulin (CRT) linked to human papillomavirus type 16 E7 antigen (CRT/E7) in a preclinical model. Experimental Design: We characterized the combination of cisplatin with CRT/E7 DNA vaccine using different regimen for its potential ability to generate E7-specific CD8+ T-cell immune responses as well as antitumor effects against E7-expressing tumors. Results: Our results indicate that treatment of tumor-bearing mice with chemoimmunotherapy combining cisplatin followed by CRT/E7 DNA generated the highest E7-specific CD8+ T-cell immune response and produced the greatest antitumor effects and long-term survival as well as significant levels of E7-specific tumor-infiltrating lymphocytes compared with all the other treatment regimens. Furthermore, we found that treatment with cisplatin leads to the cell-mediated lysis of E7-expressing tumor cells in vitro and increased number of E7-specific CD8+ T-cell precursors in tumor-bearing mice. In addition, we observed that E7-specific CD8+ T cells migrate to and proliferate in the location of TC-1 tumors in mice treated with cisplatin. Conclusions: Thus, our data suggest that chemoimmunotherapy using cisplatin followed by CRT/E7 DNA vaccine is an effective treatment against E7-expressing tumors and may potentially be translated into the clinical arena.

Stage IC adenocarcinoma of the endometrium: survival comparisons of surgically staged patients with and without adjuvant radiation therapy.

OBJECTIVE The goal of this study was to determine the outcomes of stage IC endometrial carcinoma patients who are managed with and without adjuvant radiation therapy after comprehensive surgical staging. METHODS Patients with FIGO stage IC adenocarcinoma of the endometrium diagnosed from 1988 to 1999 were identified from tumor registry databases at four institutions. A retrospective chart review identified 220 women who underwent comprehensive surgical staging including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic/paraaortic lymphadenectomy, and peritoneal cytology. RESULTS Of the 220 stage IC patients, 56 (25%) patients received adjuvant brachytherapy (BT), 19 (9%) received whole-pelvis radiation (WPRT), and 24 (11%) received both WPRT and BT. One hundred twenty-one patients (55%) did not receive adjuvant radiation. There were 6 recurrences (6%) in the radiated group and 14 (12%) in the observation group (P = 0.20). Seven of fourteen recurrences in the observation group were local, and all local recurrences were salvaged with radiation therapy. Two of seven distant recurrences in this group were also salvaged with surgery and chemotherapy. The overall salvage rate for the observation group was 64%. There was a statistical difference in 5-year disease-free survival between the radiated and observation groups (93% vs 75%, P = 0.013). However, the 5-year overall survival was similar in the two groups (92% vs 90%, P = 0.717). CONCLUSION Adjuvant radiation therapy improves disease-free survival in surgical stage IC patients; however, overall survival is not improved with adjuvant radiation therapy since the majority of local recurrences in conservatively managed patients can be salvaged with radiation therapy.