Adoptive immunotherapy for unresectable or recurrent pancreatic cancer, using lymphokine-activated killer cells or cytotoxic T cells

Adoptive immunotherapy (AIT) has been reported to be effective for malignancies in some cases. We hypothesized that AIT may be effective for the treatment of pancreatic cancer. Seven patients with unresectable or recurrent pancreatic cancer underwent AIT, carried out with lymphokine-activated killer (LAK) cells or cytotoxic T cells (CTLS) and recombinant interleukin-2 (IL-2). The clinical and immunological effects were evaluated. Of four patients who received CTLs, one had a partial response, one had a minor response, and two showed no change. The three patients who received LAK cells had progressive disease. The CTLs had a significantly higher proportion of CD8 positive T cells and cytotoxic T cells than the LAK cells (P < 0.05), while the LAK cells had a significantly higher proportion of NK cells than did the CTLs (84 ± 12% vs 55 ± 15%,P < 0.05). The LAK activity of the CTLs (61 ± 14%) was significantly higher than that of the LAK cells (42 ± 8%,P < 0.05). Seven days after treatment with LAK cells or CTLs, lymphocyte subsets in the peripheral blood were examined. The proportion of CD8-positive T cells after CTL transfer (46 ± 5%) was greater than that before CTL transfer (28 ± 1%,P < 0.05). The proportion of cytotoxic T cells after CTL transfer increased from 23 ± 1% to 37 ± 2% (P < 0.05). However, these changes were not observed during LAK cell transfer. The proportions of suppressor inducer T cells, helper T cells, and suppressor T cells did not change during therapy. These results suggested that AIT, using CTLs, merits further clinical investigation in patients with pancreatic cancer.     

Immunological evaluation of neoadjuvant peptide vaccination before radical prostatectomy for patients with localized prostate cancer

BACKGROUND: The purpose of this study was to determine the safety and immune responses of pre-operative personalized peptide vaccine for patients with localized prostate cancer. METHOD: Ten human leukocyte antigen (HLA)-A24(+) patients with localized prostate cancer received weekly personalized peptide vaccine for six times with positive peptides (up to four kinds of peptides) from 16 kinds of vaccine candidates, followed by a retropubic radical prostatectomy (RRP). Eight patients with localized prostate cancer receiving RRP served as the control group. The serum prostate-specific antigen (PSA) level, and peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by interferon-gamma production, and peptide-reactive immunoglobulin G (IgG) using an enzyme-linked immunosorbent assay were monitored during the treatment. Distributions of CD45RO(+) cells, CD8(+) T cells, and CD20(+) B cells in tissue microarray samples were studied using an immunohistochemical technique. RESULT: The peptide vaccination was safe and well tolerated with no major adverse effects. Increased CTL response and the anti-peptide IgG titer were observed in the post-vaccination samples in 8 of 10 or 8 of 10 patients, respectively. The intensity of CD45RO(+) infiltrating cells in the vaccination group was significantly larger than that in the control group. CD8(+) T cell infiltration was seen only in the vaccinated group. CONCLUSION: Increased immune responses, at both the circulation and tumor sites in the vaccinated group, support the further development of personalized peptide vaccines for patients with localized prostate cancer.     

Intraoperative radiotherapy for head and neck and skull base cancer

BACKGROUND: The purpose of this study was to evaluate the use of intraoperative electron beam radiotherapy (IORT) as an adjuvant modality in the treatment of advanced head and neck and skull base cancer. METHODS: Between 1991 and 1996, 34 patients with squamous cell carcinoma (SCCA) and 10 patients with non-SCCA were enrolled in this prospective nonrandomized clinical trial. Most patients had been previously treated with combinations of surgery, external beam radiotherapy, and chemotherapy. The most frequent sites treated were the skull base (56%) and the neck (44%). IORT was delivered in a dedicated operating room suite with energies of 6 to 15 MeV (6 MeV most commonly used) at doses of 12.5 to 22.5 Gy. RESULTS: At 2 years overall and disease-free survival was 32% and 21%, respectively, for the SCCA patients and 50% and 40%, respectively, for the non-SCCA patients. Tumor control rates at 2 years in the IORT field were 46% for the SCCA patients and 52% for the non-SCCA patients. For squamous cell histology, survival in patients with microscopic residual tumor did not differ from those with no residual tumor, but they both had significantly longer disease-free survival than those patients with gross residual at the time of IORT (p =.03), with a trend toward longer overall survival (p =.09). The only complication directly attributable to IORT was a neuropathy in a patient who received an IORT dose of 22.5 Gy (cumulative dose 130.1 Gy). CONCLUSIONS: IORT at a dose of 12.5 Gy is safe and produces tumor control and survival for patients likely to have microscopic residual disease in sites difficult to resect such as the skull base.     

Glutathione S-transferase polymorphisms and survival from head and neck cancer

BACKGROUND: The purpose of this study was to evaluate the prognostic ability of polymorphisms of three genes involved in the metabolism of tobacco carcinogens (GSTT1, GSTM1, GSTP1) and one polymorphism of a DNA repair gene (XRCC1) for patients diagnosed with squamous cell carcinoma (SCC). METHODS: Cox proportional hazard models were used to estimate risk of death for a prospective cohort of 190 patients. RESULTS: Individuals with the GSTT1 functional genotype were twice as likely to die from any cause (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.13-4.97) and were three times as likely to die from SCC (HR, 3.4; 95% CI, 1.33-8.41) after adjustment for age, primary therapy, and stage of disease. The XRCC1 399 Gln genotype was predictive of disease recurrence. CONCLUSIONS: Our findings, from one of the first studies to examine this research question, suggest that genomic markers of carcinogen metabolism and DNA repair capability may serve as prognostic indicators of disease recurrence and death.     

Single‐marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase

Background

In accord with the cancer stem cell (CSC) theory, only a small subset of cancer cells are capable of forming tumors. We previously reported that CD44 isolates tumorigenic cells from head and neck squamous cell cancer (HNSCC). Recent studies indicate that aldehyde dehydrogenase (ALDH) activity may represent a more specific marker of CSCs.

Methods

Six primary HNSCCs were collected. Cells with high and low ALDH activity (ALDH^high/ALDH^low) were isolated. ALDH^high and ALDH^low populations were implanted into NOD/SCID mice and monitored for tumor development.

Results

ALDH^high cells represented a small percentage of the tumor cells (1% to 7.8%). ALDH^high cells formed tumors from as few as 500 cells in 24/45 implantations, whereas only 3/37 implantations of ALDH^low cells formed tumors.

Conclusions

ALDH^high cells comprise a subpopulation cells in HNSCCs that are tumorigenic and capable of producing tumors at very low numbers. This finding indicates that ALDH activity on its own is a highly selective marker for CSCs in HNSCC. © 2010 Wiley Periodicals, Inc. Head Neck, 2010     

Current understanding of cancer stem cells: Review of their radiobiology and role in head and neck cancers

Evidence of cancer cells that bear attributes analogous to those of normal stem cells has developed a hierarchical model of cancer's architecture and progression. This subset of cancer stem cells (CSCs) drives the progression and therapy resistance of cancers. Research to identify the phenotypes of these CSCs presents evidence of a subpopulation that is more resistant to therapy and may proliferate in response. Literature shows that CSCs typically represent around 1%‐10% of cell populations in head and neck cancer but this proportion may increase in response to a therapeutic radiation dose. This is shown to be not just as a result of preferential killing, but also their capacity to alter divisional dynamics and enlist the support of a complicit microenvironment in therapy resistance and proliferation. The CSCs represent the apex of a hierarchy in the heterogeneity of cancer cells and may be seen as the agents of treatment failure, metastasis, and tumor recurrence, the principal cause of mortality in head and neck cancers. Greater than 90% of head and neck cancers are squamous cell carcinomas (HNSCCs), and among these an increasing incidence of the involvement of the human papillomavirus (HPV) is reported. Chemoradiotherapy along with surgical resection are the interventions of choice for control and cure of HNSCC, but given CSCs therapy resistance and proliferative responses to radiation, the identification and understanding of the radiobiology of this subpopulation is critical to their targeted elimination. This article reviews the current evidence on CSC generally and in HNSCC specifically to identify their phenotype, evaluate their responses to radiotherapy, and evaluate the defensive mechanisms used to resist therapeutic control.     

淋巴细胞与肝癌细胞混合培养诱导特异性细胞毒T淋巴细胞的形成

目的 通过肝癌细胞和淋巴细胞混合培养，体外诱导产生高活性的肝癌特异性细胞T淋巴细胞（H－S－CTL）。方法 采用淋巴细胞和肝癌细胞混合培养技术，在IL－1，IL－2，IL－4和IL－6刺激下，诱导产生H－S－CTL，应用间接免疫荧光法和^51Cr释放法检测其对靶细胞的杀伤效应。结果 H－S－CTL与自身LAK相比，CD3＋，CD4＋和CD8＋细胞明显增多，抗肿瘤效应明显增强。结论 采用淋巴细胞和肝癌细胞混合培养同时应用白细胞介素可获得大量扩增的高活性的H－S－CTL。     

Alloantigen gene therapy for head and neck cancer: evaluation of animal models

BACKGROUND: Human trials of alloantigen gene therapy, using the class I major histocompatibility complex (MHC) HLA-B7, have demonstrated the potential efficacy of this treatment for head and neck cancer. Its mechanism remains unclear. An immune-competent mouse model of MHC gene therapy to test factors potentially important to the tumor response is needed. METHODS: Two cell lines were used, B4B8 cells that grow in Balb/c mice and SCC-VII cells that grow in C3H mice. The mouse MHC H2-K(b) was used as the therapeutic gene, because it is an alloantigen to both mice strains. Plasmids that encode the H2-K(b) cDNA were prepared, and the cell lines were transfected. Mice were injected subcutaneously with naive cells to determine the tumor kinetics and serve as controls. Mice were injected with H2-K(b) transfected cells and tumor growth was compared with controls. Mice that did not grow tumor were rechallenged with naive cells to assess for tumor immunity. Mice were injected with transfected and naive cells admixed to determine whether the concentration of the alloantigen is important. RESULTS: B4B8 tumors grew slowly, whereas SCC-VII tumors grew rapidly. Transfection with H2-K(b) plasmid prevented or inhibited tumor growth of both the B4B8 and SCC-VII tumors. This growth inhibition was independent of the number of cells injected. In the mice that did not grow tumor, tumor immunity was demonstrated after challenge with naive cells in both models. There was no relationship between induction of immunity and the timing of the challenge or initial cell quantity. The mice injected with a mixture of naive and transfected cells grew tumor, although growth was delayed in the B4B8 model. CONCLUSIONS: The results demonstrate that the two mouse models can serve as a rapid and slow growing tumor model of alloantigen gene therapy. In addition, it was noted that initial tumor cell number is not a significant factor for predicting tumor response and demonstrated that in both of these models alloantigen gene therapy results in significant antitumor immunity.     

Clinical development of immunotherapy for prostate cancer

Prostate cancer is the most common cancer in men, and the second leading cause of cancer‐related death in Western countries. Prostate cancer‐related death occurs in patients with metastatic castration‐resistant prostate cancer. Although several new drugs for castration‐resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed.     

Designing biomarker studies for head and neck cancer

Although there is ample literature reporting on the identification of molecular biomarkers for head and neck squamous cell carcinoma, none is currently recommended for routine clinical use. A major reason for this lack of progress is the difficulty in designing studies in head and neck cancer to clearly establish the clinical utility of biomarkers. Consequently, biomarker studies frequently stall at the initial discovery phase. In this article, we focus on biomarkers for use in clinical management, including selection of therapy. Using several contemporary examples, we identify some of the common deficiencies in study design that hinder success in biomarker development for this disease area, and we suggest some potential solutions. The purpose of this article is to provide guidance that can assist investigators to more efficiently move promising biomarkers in head and neck cancer from discovery to clinical practice. © 2013 Wiley Periodicals, Inc. Head Neck 36: 1069–1075, 2014     

Importance of the immune system in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) are a heterogeneous group of tumors, mainly caused by exposure to cigarette smoke and/or alcohol. In recent years, a virally driven subset of cancers driven by human papillomavirus subtype 16 [HPV‐16]) has emerged. Our own data and data from other groups have demonstrated the favorable clinical outcome of HPV‐driven oropharyngeal tumors and in both HPV+ and HPV? cancers the importance of a high density of tumor‐associated lymphocytes for survival. These data underpin manipulation and activation of the patients' immune system by treatment, and as a result immunotherapy is rapidly taking its place in the management of HNSCC. Here we review the role the immune system in relation to HNSCC and consider the implications these have for HNSCC immunotherapy. Studies to quantify survival benefits and treatment‐associated toxicities are ongoing.     

Selective neck dissection in the management of the neck after (chemo)radiotherapy for advanced head and neck cancer. Proposal for a classification update

For patients with advanced regional disease, neck dissection following (chemo)radiotherapy remains controversial. Selective neck dissection (SND) was reported as suitable after chemoradiation in patients with advanced regional disease. Reduced morbidity represents the major advantage of SND. In a situation in which there is a major fibrosis around the previously invaded nodes, resection of 1 or more nonlymphatic structures may be required. The current classification of SND could be implemented by the addition of extended selective neck dissection (ESND). The standard basic procedures for SND spare the sternocleidomastoid muscle (SCM), the internal jugular vein (IJV), and the spinal accessory nerve (SAN). When an SND is associated with the resection of 1 or more nonlymphatic structures, it should be termed ESND. All additional nonlymphatic structure(s) removed should be identified in parentheses. The proposal to subclassify SND not only in accord with the resected lymph node levels but also upon the nonlymphatic structures removed may be of some help to avoid potential misinterpretation. © 2010 Wiley Periodicals, Inc. Head Neck, 2010