Loveleen Kang

Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer

Antigen-specific CD8+ T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms of tumor escape. Using in vivo models, we show here that MDSCs directly disrupt the binding of specific peptide–major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration of tyrosines in a T-cell receptor (TCR)-CD8 complex. This process makes CD8-expressing T cells unable to bind pMHC and to respond to the specific peptide, although they retain their ability to respond to nonspecific stimulation. Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact. Molecular modeling suggests specific sites of nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC. These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent to many pathological conditions associated with accumulation of MDSCs.

Bladder cancer: a review of non-muscle invasive disease.

BACKGROUND Bladder cancer is one of the most common cancers affecting men and women and thus has a profound impact on health care. The majority of patients (75%) with newly diagnosed urothelial tumors have non-muscle invasive disease confined to the bladder mucosa or the lamina propria. METHODS The authors review the literature as well as recently published clinical guidelines regarding the bladder cancer risk and causative factors, diagnostic and pathologic evaluation, prognostic variables, and management strategies for patients with non-muscle invasive bladder cancer. RESULTS Recurrence and progression remain problematic for many patients and are dependent on multiple clinical and pathological features, the most important of which are tumor stage, grade, multifocality, size, recurrence patterns, and the association with carcinoma in situ. Accurate assessment of clinical stage and tumor grade is critical in determining management and surveillance strategies. Intravesical therapies positively influence tumor recurrence rates. Disease progression rates may be impacted in high-risk patients who receive both induction bacille Calmette-Guérin (BCG) and a maintenance BCG regimen. Cystectomy still plays a pivotal role in patients with high-risk tumors and in patients who fail more conservative attempts to eradicate non-muscle invasive disease. CONCLUSIONS Non-muscle invasive bladder cancers represent a broad group of tumors with varying biologic potential. Successful treatment depends on the careful integration of diagnostic and surveillance tests, macroablation through transurethral resection, accurate assessment of clinical stage, and the timely and appropriate delivery of intravesical chemotherapeutic and immunomodulatory agents.

Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-cell Neoplasms

Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma). Experimental Design: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted. Results: Sixteen patients were treated. The MTD was established as 1.3 mg/m2 for bortezomib and 30 mg/m2 for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results. Conclusions: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non–Hodgkins lymphoma, justifying phase II studies to determine the activity of this regimen more definitively. Clin Cancer Res; 17(10); 3388–97. ©2011 AACR.

Lack of BK virus DNA sequences in most transitional‐cell carcinomas of the bladder

BK virus (BKV), a common human polyomavirus infection latent in the kidneys, can reactivate with immunosuppression to cause renal disease. Some have suggested that BKV may contribute to the development of bladder cancer, and BKV sequences have been reported from bladder tumors. To further examine the role of BKV in human bladder cancer, a series of bladder tumors was investigated for BKV genomic sequences. Fresh‐frozen specimens from 76 transitional cell carcinoma tissues and 46 paired adjacent normal urothelial tissues archived at the H. Lee Moffitt Cancer Center were studied. All tissues were histopathologically reviewed. DNA extracted from the tissues was tested by quantitative real‐time polymerase chain reaction (QPCR) assays to detect BKV DNA sequences in the VP1 coding region. Amplification of ERV‐3 was conducted separately to quantify cell copy number. Conventional PCR targeting the BKV T‐antigen (T‐Ag) coding region and immunohistochemistry for BKV T‐Ag were also conducted on all tissues that tested positive for BKV by QPCR. Seventy‐three bladder tumors yielded ≥3,000 copies of ERV‐3, 4 (5.5%) of which tested positive for BKV with average copy numbers of 7.9, 15.8, 0.4 and 0.3 per 1,000 cells. Paired normal tissue was available for 2 of these BKV‐positive tumors, 1 of which was BKV‐positive (14.6 copies/1,000 cells). No other normal tissues were BKV‐positive by QPCR. The 6 BKV‐positive tissues by QPCR were also positive by conventional PCR, but all stained negative for BKV T‐Ag by immunohistochemistry. BKV is unlikely to be involved in the etiology of most bladder tumors.

Randomized, Placebo-Controlled Trial of Green Tea Catechins for Prostate Cancer Prevention

Preclinical, epidemiologic, and prior clinical trial data suggest that green tea catechins (GTC) may reduce prostate cancer risk. We conducted a placebo-controlled, randomized clinical trial of Polyphenon E (PolyE), a proprietary mixture of GTCs, containing 400 mg (−)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). The primary study endpoint was a comparison of the cumulative one-year prostate cancer rates on the two study arms. No differences in the number of prostate cancer cases were observed: 5 of 49 (PolyE) versus 9 of 48 (placebo), P = 0.25. A secondary endpoint comparing the cumulative rate of prostate cancer plus ASAP among men with HGPIN without ASAP at baseline, revealed a decrease in this composite endpoint: 3 of 26 (PolyE) versus 10 of 25 (placebo), P < 0.024. This finding was driven by a decrease in ASAP diagnoses on the Poly E (0/26) compared with the placebo arm (5/25). A decrease in serum prostate-specific antigen (PSA) was observed on the PolyE arm [−0.87 ng/mL; 95% confidence intervals (CI), −1.66 to −0.09]. Adverse events related to the study agent did not significantly differ between the two study groups. Daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year accumulated in plasma and was well tolerated but did not reduce the likelihood of prostate cancer in men with baseline HGPIN or ASAP. Cancer Prev Res; 8(10); 879–87. ©2015 AACR.

Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy

Purpose The purpose of this Phase II randomized-controlled trial was to evaluate the safety and effect of administering several doses of lycopene to men with clinically localized prostate cancer, on intermediate endpoint biomarkers implicated in prostate carcinogenesis. Methods Forty-five eligible men with clinically localized prostate cancer were supplemented with 15, 30 or 45 mg of lycopene or no supplement from biopsy to prostatectomy. Compliance to study agent, toxicity, changes in plasma lycopene, serum steroid hormones, PSA and tissue Ki-67 were analyzed from baseline to completion of intervention. Results Forty-two of forty-five five subjects completed the intervention for approximately 30 days from the time of biopsy until prostatectomy. Plasma lycopene increased from baseline to post treatment in all treatment groups with greatest increase observed in the 45 mg lycopene-supplemented arm compared to the control arm without producing any toxicity. Overall, subjects with prostate cancer had lower baseline levels of plasma lycopene similar to those observed in previous studies in men with prostate cancer. Serum free testosterone decreased with 30 mg lycopene supplementation and total estradiol increased significantly with 30 mg and 45 mg supplementation from baseline to end of treatment, with no significant increases in serum PSA or tissue Ki-67. These changes were not significant compared to the control arm for this sample size and duration of intervention. Conclusions Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, our study suggests that other mechanisms mediated by steroid hormones may also be involved.

Serial assessment of lymphocytes and apoptosis in the prostate during coordinated intraprostatic dendritic cell injection and radiotherapy

Local radiotherapy plus intratumoral syngeneic dendritic cell injection can mediate apoptosis/cell death and immunological tumor eradication in murine models. A novel method of coordinated intraprostatic, autologous dendritic cell injection together with radiation therapy was prospectively evaluated in five HLA-A2(+) subjects with high-risk, localized prostate cancer, using androgen suppression, 45 Gy external beam radiation therapy in 25 fractions over 5 weeks, dendritic cell injections after fractions 5, 15 and 25 and then interstitial radioactive seed placement. Serial prostate biopsies before and during treatment showed increased apoptotic cells and parenchymal distribution of CD8(+) cells. CD8(+) T-cell responses to test peptides were assessed using an enzyme-linked immunosorbent spot IFN-γ production assay, demonstrating some prostate cancer-specific protein-derived peptides associated with increased titer. In conclusion, the technique was feasible and well-tolerated and specific immune responses were observable. Future trials could further test the utility of this approach and improve on temporal coordination of intratumoral dendritic cell introduction with particular timelines of therapy-induced apoptosis.

Phase I Trial of Bortezomib (PS-341; NSC 681239) and “Nonhybrid” (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms

Purpose: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). Experimental Design: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigators discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. Results: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m2 for bortezomib and 40 mg/m2 for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses. Conclusions: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies. Clin Cancer Res; 20(22); 5652–62. ©2014 AACR.

Pure laparoscopic and robotic-assisted laparoscopic radical prostatectomy in the management of prostate cancer.

BACKGROUND Until recently, open radical prostatectomy was the only approach for the surgical management of prostate cancer. Laparoscopy is now increasingly used as an alternative approach. The procedure can be performed directly or with robot assistance. METHODS We review the relevant literature regarding oncologic and functional outcomes with laparoscopic surgery in the management of localized prostate cancer. RESULTS Oncologic and functional outcomes are similar between open and laparoscopic radical prostatectomy. Pure laparoscopic prostatectomy and robotic assisted laparoscopic prostatectomy result in less blood loss and shorter convalescence. Costs associated with the initial investment, disposables, and maintenance of the robot system are higher than for pure laparoscopic prostatectomy. CONCLUSIONS Laparoscopic radical prostatectomy, either pure or robotic, is becoming the preferred approach for the surgical management of localized prostate cancer. Oncologic and functional outcomes are similar to the open approach.

B-Lymphoblastic Leukemia/Lymphoma Associated with t(8;13)(p11;q12)/ZMYM2 (ZNF198)-FGFR1: Rare Case and Review of the Literature

Myeloid and lymphoid neoplasms with fibroblastic growth factor receptor-1 (FGFR1) abnormalities originate from mutated pluripotent stem cells and have a heterogeneous clinical presentation. There are 12 identified partner genes commonly involved in FGFR1 translocation at an 8p11 breakpoint. In FGFR1-related neoplasms, T-lymphoblastic lymphoma with eosinophilia is the most common clinical scenario, whereas acute B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is rare. To date, only 7 cases of B-ALL/LBL with FGFR1 abnormalities have been reported. Here, we report an additional case of a 64-year-old gentleman with leukocytosis, eosinophilia and diffuse mediastinal and general lymphadenopathy. Bone marrow examination showed patchy infiltrates of immature precursors/blasts, along with myeloid/eosinophilic hyperplasia. Immunophenotyping confirmed increased B lymphoblasts (30-40%). Karyotyping revealed cytogenetic abnormalities, including t(8;13)(p11;q12)/ZMYM2 (ZNF198)-FGFR1 and trisomy 21. The patient did not respond to hyper-CVAD chemotherapy and within 4 months developed acute myelomonocytic leukemia and expired 11 months after the initial diagnosis. Similar cases from the literature are reviewed.