Induction therapy of loco-regional non-small-cell lung cancer with reliable response and low toxicity (low dose radiotherapy sensitizes tumor to subsequent chemotherapy?).

INTRODUCTION: For the induction therapy of non-small-cell lung cancer, we need to look for a regimen which produces a reliable high response rate with a low treatment related morbidity and mortality. METHODS: Patients in clinical stages IB, IIA and B, IIIA and B received a course of therapy with 20Gy of radiation in 2 weeks. This was followed by two courses of chemotherapy consisting of paclitaxel 180mg/m(2), cisplatin 45mg/m(2), and ifosfamide 1000mg/m(2). Two to 3 weeks after chemotherapy, the patients were re-evaluated and, if suitable, underwent surgical therapy. RESULTS: A total of 35 patients were entered into the study. The overall response rate was 82.86% (95% confidence interval, 66.35-94.5%). Complete response (CR) was 20% (95% confidence interval, 8.44-36.94%). Twenty-five patients had surgical resection. Subsequently 18 patients received completion radiotherapy of additional 45Gy. The median follow up is 30 months. In 12 patients with stages IB, IIA and B, the median survival was 61 months, and 5-year survival was 55%. In 23 patients with stages IIIA and B, the median survival was 26 months, and 5-year survival was 9.5%. There was 1 patient with Grade 4 and 13 patients with Grade 3 leukopenia, and half of them received granulocyte colony stimulating factor. By the completion radiotherapy, 6 out of 18 patients had less than Grade 2 esophagitis. Five patients had Grade 2 radiation pneumonitis and one Grade 5 (one mortality). There was no postoperative death. The survival results were comparable to those reported recently by others, however the regimen produced a high response rate with low treatment related morbidity/mortality. CONCLUSION: It is a suitable regimen for induction therapy to include earlier stage resectable non-small-cell lung cancers.

Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model.

BACKGROUND: The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs), has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. METHODS: To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I (+) lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8(+) CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. RESULTS: The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-gamma, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. CONCLUSION: These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular immunotherapy as effector cells seek and destroy areas of tumor growth and for testing strategies to improve clinical effectiveness.

Human CD4+ effector T cells mediate indirect interleukin-12- and interferon-gamma-dependent suppression of autologous HLA-negative lung tumor xenografts in severe combined immunodeficient mice.

A human/severe combined immunodeficient mouse chimeric model was used to demonstrate that peripheral blood leukocytes (PBLs) from a patient with lung cancer completely suppress the growth of an autologous tumor in a PBL dose-dependent fashion repeatedly and over a 4-year period. Suppression of the patient's tumor required CD4+ T cells, CD56+ natural killer cells, and CD14+ monocytes/macrophages, but was completely independent of CD8+ T cells. The CD4+ effector cells promoted tumor killing indirectly because direct tumor recognition and killing are precluded by the absence of MHC class I and II molecules on the tumor cells. Tumor suppression was found to require both human interleukin-12 (IL-12) and IFN-gamma, which were produced and released by the patient's monocytes and T cells, respectively. These results establish that human CD4+ T cells present in the peripheral blood of a patient with lung cancer are able to orchestrate cytokine-dependent killing of an autologous MHC-negative tumor indirectly and without codependence on CD8+ T cells. We conclude that human tumor suppression is achieved in vivo even in the absence of MHC molecules on tumor cells. This tumor suppression is mediated indirectly by cytokines produced by the patient's PBLs that ultimately initiate tumor killing via several, presently incompletely defined mechanisms.

Cytokines and chemokines are expressed at different levels in small and large murine colon-26 tumors following intratumoral injections of CpG ODN.

Direct tumor injections of (CpG ODN) into murine colon tumor 26 (CT-26) tumors can induce a potent antitumor response. Tumor size at the beginning of treatment determines the final therapeutic outcome, with smaller tumors responding favorably to CpG ODN therapy whereas large tumors do not. CpG ODN injections in small tumors resulted in tumor necrosis and extensive inflammatory cell infiltration, with average survival that is significantly higher (48.1 +/- 34 days) when compared to control ODN-treated mice (16.1 +/- 3.5 days). Cytokines and chemokines are expressed at different levels in small and large CT-26 tumors following intratumoral injections of CpG ODN. We observed that granulocyte-macrophage colony-stimulating factor and interleukin (IL) 6 are the major cytokines that were overexpressed in CpG ODN-treated small tumors but not in large tumors. Similarly, several chemokines (CXCL1, CCL2, and CCL3) were also significantly higher in CpG ODN-treated small tumors compared to control ODN-treated tumors.

Discharge independence with minimally invasive lobectomy.

BACKGROUND: The effects of video-assisted thoracic surgery (VATS) pulmonary lobectomy on after-hospital care are not well known. METHODS: In a retrospective case-control study, 20 consecutive VATS cases were matched to 38 standard thoracotomies (open cases). RESULTS: Ages were 73.8 +/- 7.8 years with no initial differences between the groups. No hospital deaths occurred. Excluding 2 VATS and 6 open outliers, VATS cases had fewer hospital days (4.6 +/- 1.9 vs. 6.4 +/- 2.2, P <0.01), chest tube days (3.0 +/- 1.1 vs. 4.2 +/- 1.7, P = 0.01), and prolonged pain complaints (28% vs. 56%, P = 0.05). Transfer to care facilities or home nursing support was needed for 63% of open patients and only 20% of VATS patients (P = 0.015). Less personal care (10% vs. 21%), wound/medical care (0% vs. 13%), occupational/physical therapy (5% vs. 13%), or other home support (5% vs. 18%) was needed for VATS patients. CONCLUSIONS: In older populations, more independence and fewer resources after discharge favor VATS lobectomy over standard thoracotomy.

Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice.

Non-disrupted pieces of primary human lung tumor implanted into NOD-scid IL2Rgamma(null) mice consistently result in successful xenografts in which tissue architecture, including tumor-associated leukocytes, stromal fibroblasts, and tumor cells are preserved for prolonged periods with limited host-vs-graft interference. Human CD45(+) tumor-associated leukocytes within the xenograft are predominantly CD3(+) T cells with fewer CD138(+) plasma cells. The effector memory T cells that had been shown to be quiescent in human lung tumor microenvironments can be activated in situ as determined by the production of human IFN-gamma in response to exogenous IL-12. Plasma cells remain functional as evidenced by production of human Ig. Significant levels of human IFN-gamma and Ig were detected in sera from xenograft-bearing mice for up to 9 wk postengraftment. Tumor-associated T cells were found to migrate from the microenvironment of the xenograft to the lung, liver, and primarily the spleen. At 8 wk postengraftment, a significant portion of cells isolated from the mouse spleens were found to be human CD45(+) cells. The majority of CD45(+) cells were CD3(+) and expressed a phenotype consistent with an effector memory T cell, consisting of CD4(+) or CD8(+) T cells that were CD45RO(+), CD44(+), CD62L(-), and CD25(-). Following adoptive transfer into non-tumor bearing NOD-scid IL2Rgamma(null) mice, these human T cells were found to expand in the spleen, produce IFN-gamma, and maintain an effector memory phenotype. We conclude that the NOD-scid IL2Rgamma(null) tumor xenograft model provides an opportunity to study tumor and tumor-stromal cell interactions in situ for prolonged periods.

IL-12 reverses anergy to T cell receptor triggering in human lung tumor-associated memory T cells.

Memory T cells in human non-small cell lung cancer are unresponsive to progressing tumors. T cells were evaluated at the single cell level by imaging the nuclear translocation of NF-kappaB and NFAT via immunofluorescence confocal microscopy as an early measure of responsiveness to T cell receptor triggering. Little translocation of NF-kappaB or NFAT occurred in tumor-associated T cells in response to CD3+CD28 cross-linking under conditions which led to maximal translocation in normal donor peripheral blood T cells. TNF-alpha induced maximal NF-kappaB translocation in these T cells, indicating that they remain receptive to alternative signaling pathways, and pulsing with IL-12 prior to TCR triggering reversed their apparent anergy. T cells from additional chronic inflammatory microenvironments demonstrated a similar refractoriness to TCR activation, suggesting either that a common regulatory mechanism present within the microenvironment controls these cells or that with continuous antigen exposure, they remain refractory to activation via the TCR.

Intra-tumoral injection of CpG results in the inhibition of tumor growth in murine Colon-26 and B-16 tumors.

Direct tumor injections of CpG (ODN #1826) into murine tumors markedly suppressed the tumor growth and increased the survival of the mice. Tumor growth was reduced by 60-67% in Colon Tumor 26 (CT-26) and B-16 melanoma tumors treated with CpG as compared to untreated one. In CT-26 and B-16 tumors treated with CpG, the average survival of the animals were prolonged to 26 and 28 d as compared to 16 and 18 d in control respectively. Long-term surviving animals in CT-26 tumor groups were also protected from a subsequent injection of a lethal dose of tumor cells. In the present study, effect of CpG was mediated through CD8+ T cells, as their depletion resulted in the abrogation of the therapeutic effects of the CpG. It suggests that direct tumor injection might be a simple means of achieving a clinical response in cancer patients.