New insights into tumor-host interactions in lymphoma metastasis

The metastatic process is characterized by a complex series of sequential steps involving constant interactions (mutual cross-talks) of metastasized tumor cells with their microenvironment (lymphocyte, macrophages, endothelial cells, etc.) in target organs. These interactions determine the outcome of metastasis (either the eradication of metastatic cells or their increased proliferation and invasion). Recently developed methods of tumor and host cell analysis at the molecular level allow better elucidation of molecular mechanisms of metastasis and of immune mechanisms involved in antitumor responses. Direct modulation of these processes will probably increase the success of clinical cancer treatment. Here we review data (a) on the expression of some costimulatory (MHC class II, CD80, sialoadhesin) and adhesion (LFA1, ICAM-1, VLA-4) molecules on both metastasized tumor cells and host cells and (b) on the production of a cytotoxic molecule, nitric oxide, by in situ activated Kupffer and endothelial cells in the process of liver metastasis. This study was performed with well-characterized murine ESbL T lymphoma cells transduced with the bacterial lacZ gene, which allows detection and quantification of metastases at the single cell level throughout lymphoma growth and metastasis. Experimental results are discussed in the context of recent literature.Abbreviations APC Antigen-presenting cells - hCRP Human C-reactive protein - ICAM Intercellular adhesion molecule - IFN Interferon - IL Interleukin - iNOS Inducible NO synthase - LFA Leukocyte function associated antigen - SER Sheep erythrocyte receptor - TA Tumor-associated rejection antigens - TNF Tumor necrosis factor - VCAM Vascular cell adhesion molecule - VLA Very late activated antigen     

特瑞普利单抗联合舒尼替尼治疗晚期肾细胞癌的初步疗效分析

目的：评估特瑞普利单抗联合舒尼替尼治疗晚期肾细胞癌的疗效与安全性。方法：回顾性分析2020年1月—2022年3月海军军医大学第二附属医院接受特瑞普利单抗联合舒尼替尼治疗的25例晚期肾癌患者临床资料,其中男21例,女4例,中位年龄为59 (33~80)岁。25例患者病理类型均为透明细胞癌,其中2例为TFE3融合基因相关肾癌,1例部分肉瘤样变,25例患者均发生局部进展或远处转移。评价其生存获益和相关不良反应发生情况。结果：中位随访时间11.0(2.5～24)个月,25例患者均可评价疗效,总体人群ORR 36.0%,DCR 84.0%,9例患者部分缓解,12例患者病情稳定,4例患者疾病进展,中位PFS 12.7个月(95%置信区间：10.7～14.7),中位OS尚未达到。治疗总体不良反应发生率为88.0%,常见不良反应包括皮疹、腹泻、手足皮肤反应、高血压等,90%的不良反应为1~2级。     

Immune adjuvants for chemotherapy or radiotherapy in the 9L rat brain tumor model

Summary The therapeutic efficacy and toxicity of three biological response modifiers,Corynebacterium parvum (Cp), Chinese blister beetle extract (CBBE), recombinant human IL-1 (rhIL-1), used alone or in combination with chemotherapy or radiotherapy, were investigated in the intracerebral (ic) rat 9L brain tumor model. Used alone, Cp (2mg/rat, ip plus 70g/rat, ic), CBBE (5l of an ethanol extract, ic), or IL-1 (lg/rat, ic or 1g/rat × 3, q 3 d, ic), had no effect on animal survival compared to the untreated or saline treated controls. When combined with chemotherapy or radiotherapy, the three immunotherapeutic agents did not show any additive effects on survival compared to that observed with systemic BCNU (12mg/kg), local ic bleomycin (0.25 unit), or local radiotherapy (16 Gy). While ic IL-1 did not produce evident toxicity, there was fatal toxicity caused by ic Cp or CBBE treatment in a few animals. The combination of Cp and bleomycin produced severe neurotoxicity, resulting in the early death of animals. This study demonstrates a lack of efficacy of the nonspecific immune adjuvants IL-1, Cp or CBBE, used either alone or combined with cytotoxic chemotherapy or radiotherapy, in this rat brain tumor model.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Cytokine production by the human bladder carcinoma cell line T24 in the presence of bacillus Calmette-Guerin (BCG)

Summary The study was initiated as an in vitro approach to the situation existing during intravesical bacillus Calmette-Guerin (BCG) instillation in patients with superficial bladder cancer. Cytokine secretion of a human bladder carcinoma cell line T24 treated with BCG was investigated. A 24-h treatment of T24 cells with BCG resulted in a tenfold higher secretion of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF) when compared with T24 cells treated with Escherichia coli, Streptococcus faecalis or a cell wall preparation of Nocardia rubra (N-CWS). No secretion of IL-1 and IL-2 was detected. Pre-exposing T24 cells to BCG for various periods of time indicated that a minimum exposure time of 0.5–1 h was required to upregulate IL-6 and TNF production. Extending the BCG pre-exposure time to 2 and 3 h further increased the rate of cytokine production. No significant difference was found, however, between the rate of secretion initiated after a 2-h or 3-h pre-exposure period. The amounts of these cytokines secreted in the presence of BCG-conditioned medium did not differ significantly from the constitutively secreted amounts, excluding an effect of products possibly secreted by BCG on the upregulation of IL-6 and TNF. In addition, upregulation of cytokine production appeared to be dependent on the concentration of BCG. The results suggest that cytokines may be produced by urothelial tumor cells after intravesical instillation in patients with superficial bladder cancer, which may play a role in the mode of action of BCG.     

梨状窝癌局部扩展的病理学研究

目的　探讨梨状窝癌局部扩展的规律 ,为梨状窝癌的手术治疗提供病理学依据。方法　应用石蜡包埋大体标本连续切片的方法 ,对 2 6例梨状窝癌全喉及次全喉切除的标本进行了观察。结果　位于梨状窝外侧壁的肿瘤 ( 4例 )主要向外侧咽侧壁扩展 ,位于梨状窝内侧壁的肿瘤 ( 5例 )容易向喉腔及对侧梨状窝扩展。累及整个梨状窝 17例。声门旁间隙及甲状软骨是最易受侵犯的喉结构 ,环状软骨受侵较少 ;会厌及会厌前间隙的侵犯未见超过中线 ,声门旁间隙及会厌前间隙的侵犯途径有2个 ,肿瘤沿杓会厌襞向前及在甲状软骨板内侧直接向前侵犯声门旁间隙 ;肿瘤沿杓会厌襞向内上方及在甲状软骨板内侧上部侵入会厌前间隙。结论　会厌前间隙的受侵并不是喉部分切除的禁忌证 ,大部分位于梨状窝外侧壁的肿瘤及部分梨状窝内侧壁的肿瘤保留喉功能是可行的 ;位于梨状窝内侧壁及环后区的肿瘤易在环后区向对侧侵犯 ,对累及环后区的梨状窝癌 (Ⅰ ,Ⅲ型 ) ,应注意肿瘤在环后区粘膜下向对侧侵犯。     

Immunotherapeutic targets in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the most common types of cancer in the world and has a 5-year survival rate of ~20%. Immunotherapies have shown promising results leading to durable responses, however, they are only effective for a subset of patients. To determine the best therapeutic approach, a thorough and in-depth profiling of the tumour microenvironment (TME) is required. The TME is a complex network of cell types that form an interconnected network, promoting tumour cell initiation, growth and dissemination. The stroma, immune cells and endothelial cells that comprise the TME generate a plethora of cytotoxic or cytoprotective signalling pathways. In this review, we discuss immunotherapeutic targets in NSCLC tumours and how the TME may influence patients' response to immunotherapy.     

P^27的研究概况

目的：综述Ｐ＾２７的研究进展。方法：光盘检索有关献,归纳综合整理。结果：Ｐ＾２７是细胞周期的相关蛋白,Ｐ＾２７白过度表达可抑制细胞周期的进程,阻断细胞生长于Ｇ１期。结论：Ｐ＾２７是细胞周期中重要的负性调控控因子,是一种新的侯选的肿瘤抑制基因。     

工程化纳米囊泡结合化疗用于增强肿瘤免疫治疗

目的：结合免疫治疗与化疗,以改善肿瘤的治疗效果,为安全有效的肿瘤免疫治疗策略的发展提供更多见解。方法：使用工程化纳米囊泡,囊泡膜上表达PD-1受体,可以靶向肿瘤细胞表面的PD-L1,通过破坏PD-1/PD-L1免疫抑制通路增强抗肿瘤反应。同时,囊泡包裹的化疗药物阿霉素可以进入肿瘤细胞核,抑制DNA与RNA的合成,诱导肿瘤细胞死亡。结果：实验证实,制备的PD1-阿霉素材料具备良好的稳定性、安全性,能准确靶向肿瘤部位,阿霉素在细胞核部位起作用,能有效地进行肿瘤杀伤。结论：本研究首次将PD-1免疫检查点抑制与化疗药物阿霉素相结合,利用PD-1囊泡安全性高、长循环的特点作为包裹化疗药物阿霉素的载体,这种方法可以进行肿瘤细胞的有效靶向与治疗,实现肿瘤的有效清除。     

Adoptive Immunotherapy With Tumor-Infiltrating Lymphocytes and Subcutaneous Recombinant Interleukin-2 Plus Interferon Alfa-2a for Melanoma Patients With Nonresectable Distant Disease: A Phase I/II Pilot Trial

Background: On the basis of our previous experience, we designed this study to determine the activity and toxicity of outpatient treatment with autologous tumor-infiltrating lymphocytes (TIL) together with intermediate-dose recombinant interleukin-2 (rIL-2) and low-dose recombinant interferon alfa-2a (rIFN-2a), for patients with metastatic melanoma.Methods: Between April 1992 and October 1994, we processed 38 melanoma samples derived from 36 patients with metastases. Proliferative cultures of expanded lymphocytes (TIL) were infused only once into patients with metastatic melanoma. rIL-2 was administered subcutaneously for 1 month, starting on the day of TIL infusion, at an escalating dose of 6–18 × 10⁶ IU/m²/day for the first week and at the maximum-tolerated dose for the subsequent 3 weeks and then, after a 15-day interval, for 1 week/month for 3 months. rIFN-2a was administered subcutaneously at 3 × 10⁶ IU three times each week until progression.Results: Of 38 melanoma samples, 19 (50%) resulted in proliferative cultures and were infused. The median number of expanded lymphocytes was 18 × 10⁹ (range, 1–43 × 10⁹), and the median period of culture was 52 days (range, 45–60). rIL-2 was administered at doses ranging between 6 and 18 × 10⁶ IU/m²/day. Toxicity was mild or moderate, and no life-threatening side effects were encountered. Two of 19 treated patients experienced complete responses of their metastatic sites (soft tissue), 10 had stable disease, and 7 showed progressive disease. The response rate was 11% (95% confidence interval, 2–35%).Conclusions: Outpatient treatment with TIL plus rIL-2 and rIFN-2a is feasible, although, within the context of the small sample size, the activity of the combination was no different from the reported activity of any of the components used alone.