Intratumoral Chemotherapy Research Articles

N-Butyl-2-cyanoacrylate-based injectable and in situ-forming implants for efficient intratumoral chemotherapy

The local delivery of chemotherapeutic drugs to tumor sites is an effective approach for achieving therapeutic drug concentrations in solid tumors. Injectable implants with the ability to form in situ represent one of the most promising technologies for intratumoral chemotherapy. However, many issues must be resolved before these implants can be applied in clinical practice. Herein, we report a novel injectable in situ-forming implant system composed of n-butyl-2-cyanoacrylate (NBCA) and ethyl oleate, and the sol–gel phase transition is activated by anions in body fluids or blood. This newly developed injectable NBCA ethyl oleate implant (INEI) is biodegradable, biocompatible, and non-toxic. INEI solidifies in several seconds after exposure to body fluids or blood, and the implant’s in vivo degradation time can be controlled. In addition, the pore sizes formed by the polymerization of NBCA can be decreased by increasing the NBCA concentration in the implants. Therefore, the drug retention/release time can be adjusted from a few weeks to several months by changing the concentration of NBCA in the implant formulation. Anti-tumor experiments in animal models showed that the average growth inhibition rate of xenografted human breast cancer cells by the paclitaxel-loaded INEI (40% NBCA) was 80%, and they also indicated that tumors in some of the mice were completely eliminated by just a single dosage injection. For the epirubicin-loaded INEI (50% NBCA), the average growth inhibition rate of xenografted human liver cancer cells was 58%. Thus, the chemotherapeutic drug-loaded INEIs exhibited excellent therapeutic efficacy for local chemotherapy.

Characterization and antitumor efficacy of poly(L-lactid acid)-based etoposide-loaded implants

Etoposide is widely used in the chemotherapy of a variety of malignancies. But the strong lipophilicity, poor bioavailability, and severe side effects of etoposide limit its clinical application. The aim of this study was to develop sustained-release etoposide-loaded implants and evaluate antitumor activity of the implants after intratumoral implantation. We prepared the implants containing etoposide, poly(L-lactid acid) and polyethylene glycol 4000 by the direct compression method. The implants were characterized regarding drug-excipient compatibility, content uniformity, morphology, sterility, in vitro, and in vivo release profiles. Then the antitumor activity of the implants was tested in xenograft model of A549 human non-small cell lung cancer. SEM images displayed smooth surface of the implant and indicated that etoposide was homogeneously dispersed in the polymeric matrix. The results of content uniformity met the requirements of the Chinese Pharmacopoeia. Both in vitro and in vivo release profiles of the implants were characterized by high burst release followed by sustained release of etoposide. Intratumoral implantation of etoposide-loaded implants could efficiently delay the tumor growth. Furthermore, increasing the dose of implants led to higher tumor suppression rate without adding systemic toxicity. These results indicated that etoposide-loaded implants have significant antitumor efficacy in xenograft model without dose-limiting side effects and they possess a strong potential to be used as an intratumoral chemotherapy option for lung cancer treatment.

Implantable chemotherapy-loaded silk protein materials for neuroblastoma treatment.

Neuroblastoma is the most common extracranial childhood solid tumor. Treatment of high risk tumors require intense multicycle chemotherapies, resulting in short- and long-term toxicities. Here, we present treatment of an orthotopic neuroblastoma mouse model, with silk fibroin materials loaded with vincristine, doxorubicin or the combination as a intratumoral, sustained release system. The materials, loaded with vincristine with or without doxorubicin, significantly decreased neuroblastoma tumor growth compared to materials loaded without drug or doxorubicin only as well as intravenous (IV) drug treatment. The intratumoral drug concentration was significantly higher with intratumoral delivery versus IV. Furthermore, intratumor delivery decreased the maximum plasma concentration compared to IV delivery, reducing systemic exposure and possibly reduing long-term side effects of chemotherapy exposure. Histopathologically, tumors with remission periods >25 days before recurrence transformed from a "small-round-blue cell" (SBRC) to predominantly "large cell" neuroblastoma (LCN) histopathology, a more aggressive tumor subtype with unfavorable clinical outcomes. These results show that intratumoral chemotherapy delivery may be a treatment strategy for pediatric neuroblastoma, potentially translatable to other focal tumors types. Furthermore, this treatment modality allows for a clinically relevant mouse model of tumor transformation that may be used for studying the phenotypical tumor recurrence and developing more effective treatment strategies for recurrent tumors.

Intratumoral radiofrequency hyperthermia-enhanced direct chemotherapy of pancreatic cancer.

PurposeTo investigate the technical feasibility of using ultrasound-guided intratumoral radiofrequency hyperthermia (RFH) to enhance local chemotherapy of rat orthotopic pancreatic cancers.Materials and MethodsOrthotopic pancreatic cancer masses were established by inoculating luciferase/mCherry labeled-pancreatic cancer cells into the pancreatic tails of Lewis model rats via a laparotomy approach. Twenty-four rats with pancreatic cancer and 24 mice with subcutaneous pancreatic cancer xenografts in four study groups (n = 6/group) received various treatments: i) combination therapy of intratumoral MR imaging-heating-guidewire-mediated RFH (42oC) plus local chemotherapy (gemcitabine); ii) intratumoral chemotherapy alone; iii) RFH alone; and (iv)phosphate-buffered saline (PBS). Transcutaneous ultrasound imaging was used to guide the treatment and subsequently follow changes in tumor sizes. Bioluminescence optical imaging was performed to follow photon signal changes. Sonographic and optical findings were correlated with histology at 14 days.ResultsOptical imaging demonstrated a significantly decreased bioluminescence signal in mice with combination therapy group, compared with the other control groups (0.51±0.18 VS 1.6±0.4 VS 3.18±0.9 VS 3.5±0.96, p < 0.05). Ultrasound imaging showed the smallest tumor volumes of both mice and rat group with the combination therapy, compared with other control groups (0.62±0.16 VS 1.25±0.19 VS 2.28±0.25 VS 2.64±0.26, p < 0.05) and (0.75±0.18 VS 1.31±0.30 VS 1.61±0.28 VS 1.72±0.28, p < 0.05). Both imaging findings were confirmed by histologic correlation.ConclusionIntratumoral RFH can augment the chemotherapeutic effect in an orthotopic pancreatic cancer model.

CT Guided Radiofrequency Ablation Followed Intratumoral Chemotherapy in the Treatment of Early Stage Non-small Cell Lung Cancer

背景与目的射频消融（radiofrequency ablation, RFA）已经成为无法手术的早期非小细胞肺癌（non-small cell lung cancer, NSCLC）的局部治疗方法之一。本研究观察计算机断层扫描（computed tomography, CT）引导下RFA与瘤内化疗（intratumoral chemotherapy, ITC）（RFA-ITC）的有效性和安全性。方法自2005年1月至2015年12月研究组前瞻性入组经病理学证实为早期NSCLC，因心肺功能较差或伴发其他疾病而无法耐受手术或拒绝手术的患者，接受RFA-ITC治疗。RFA采用导向器辅助CT引导穿刺准实时步进法，适形伞状电极、单点或多点消融，完成治疗计划并当CT显示肿瘤周围正常肺组织呈现磨玻璃样后结束消融治疗，经电极针将卡铂200 mg缓慢注射到肿瘤内。随访评估安全性和有效性。结果110例患者125次RFA-ITC治疗，技术成功率为100%。中位生存期为48.0个月，总生存率为55.4个月，无进展生存期为55.1个月；1年、2年、3年、5年总生存率分别为100%、90.7%、62.7%、21.9%。消融后有和无磨玻璃样改变的生存期分别是68.3个月、40.1个月，有统计学差异（P=0.001）。肿瘤的大小及有无N1分期的生存率无差异。无围手术期死亡发生，气胸、肺内出血、胸腔积液、发热、术中胸痛、皮下气肿、术中咳嗽等并发症轻微可耐受。结论CT引导RFA-ITC治疗不能手术的早期NSCLC，疗效好、并发症少，对患者损伤小，为不能手术治疗的早期NSCLC的治疗提供了一个良好方法。

Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype

The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors.

Hemiballismus as a complication of an intratumoral chemotherapy catheter

We report an unusual case of delayed bilateral, right greater than left hemiballismus in a 15-year-old female patient with a history of a craniopharyngioma 2years following the insertion of a right intratumoral chemotherapy catheter. Following cyst decompression, the catheter was found to have changed position, traversing the basal ganglia structures, namely the right subthalamic nucleus. Her movement disorder near-completely resolved immediately following removal of the catheter. A review of the current literature and proposed pathophysiological mechanisms are discussed.

Use of Hapten Combined Double Cytotoxic Drugs for Enhancing Survival Time in Large and Huge Hepatocellular Carcinoma with Comprehensive UMIPIC Therapy

Purpose: To evaluate overall survival benefit in treatment of large and huge hepatocellular carcinomas (HCC) by Ultra-Minimum Incision Personalized Intratumoral Chemoimmunotherapy (UMIPIC) compared to the Intra tumoral Chemotherapy (ITCT). Both methods include the use of two chemotherapy agents. The effect of hapten as an immune booster will also be analyzed. Materials and methods: Patients with HCC were treated with UMIPIC or ITCT, both had same therapeutic procedure, UMIPIC had a proprietary regimen composed of components includes an oxidant, a two cytotoxic drugs and hapten; ITCT delivered the same drugs but excluded hapten. Survival data of 94 patients were evaluated (n=71 for UMIPIC, n=23 for ITCT). The tumor size was classified as large tumor (5 to 10 cm) and huge tumor (>10cm), tumor sizes with liver function of Child A and B were analyzed to evaluate the correlation with overall survival time and survival rate. Results: The study revealed a significant improvement for 10 months of median overall survival in UMIPIC (Test) and 5 months in ITCT (control), respectively (P<0.05). The 6-month and 1-year survival rates of UMIPIC and ITCT were 80% vs. 32.3% and 46% vs. 22%, respectively with significantly improvement (P<0.05). The study revealed that UMIPIC has significant improvement in overall survival compared to that of ITCT for all size of HCC. There was no significant difference between patients with large and huge HCC; patient’s liver function in Child A had a better survival time compared to that of patient’s liver function in Child B in patients with UMIPIC therapy. CD3+, CD4+ and CD4+/CD8+ ratio increased following UMIPIC therapy indicating patient’s special immunity reaching a high level. Conclusion: Hapten enhanced improvement in the survival time in patients with UMIPIC therapy compared to patients with ITCT therapy. Hapten also enhanced patient’s special immunity at a high level with CD4+ and CD4+/CD8+ ratio increasing. The study revealed hapten plays an important role in UMPIC therapy to improve patient’s survival time. Liver function was also increased as indicated by results of Child A and Child B.

Hapten Improved Overall Survival Benefit in Late Stages of Non-Small Cell Lung Cancer (NSCLC) by Ultra-Minimum Incision Personalized Intratumoral Chemo Immunotherapy (UMIPIC) Therapy With and without Radiation Therapy

Aims: To evaluate overall survival time of hapten-enhanced chemo immunotherapy in the treatment of advanced NSCLC by UMIPIC with and without radiation therapy and to analyze the effective of hapten as an immune booster. Materials and Methods: 298 patients with advanced NSCLC were treated with UMIPIC or Intratumoral chemotherapy (ITCT). Some in both groups had also received radiation therapy prior to UMIPIC or ICTC. UMIPIC (86 cases) was delivered intratumorally in combination with a proprietary therapeutic regimens composed of four components including an oxidant, two cytotoxic drugs and a hapten, UMIPIC-R (115 cases) with the same procedures and added common radiation therapy. ITCT was applied the same procedures and regimens only without the hapten, ITCT-R with same procedures as ITCT and added common radiation therapy. All data from four groups were reviewed and analyzed. 201 of NSCLC patients were treated with UMIPIC, 86 of 201 NSCLC had radiation therapy, and 97 of NSCLC patients with ITCT, 48 of 97 NSCLC had radiation therapy. All patients were followed until their death and survival benefits were analyzed. Some biopsies were taken for immunohistochemical staining and observation under electronic microscopy. Results: Median survival time (OS) was 20 months in UMIPIC (test) and 7 months in ITCT (control) (P <0.001) and 6-months and 1-year year survival rate of the UMIPIC and ITCT were 95.3% vs. 61.6% (P <0.001) and 86 % vs. 32.7% (P <0.001), 2-years survival rate of the UMIPIC and ITCT were 37.2% vs. 6.5% (P <0.01) respectively. For groups with radiation therapy, median survival time (OS) was 16 months in UMIPIC-R (test with radiation therapy) and 7 months in ITCT-R (control with radiation therapy) (P<0.05), 6-months and 1-year year survival rate of the UMIPIC-R and ITCT-R were 97.4% vs. 62.5% (P<0.001) and 76.5% vs. 37.5% (P <0.001), 2-years survival rate of the UMIPIC-R and ITCT-R were 36.5% vs. 18.8% (P <0.05) respectively. Also it was revealed that dendritic cells and CD4+, CD8+ in the immunohistochemical staining and observation in EM (Figure 4), further confirmed more activities of immunological response induced by UMIPIC. Conclusion: Hapten improved clinical survival benefits by UMIPIC with hapten and double cytotoxic drugs conferred a superior survival time for patients with advanced NSCLC compared to ITCT with or without multi fractional radiation therapy. The addition of the hapten in UMIPIC with double drugs demonstrated a significant improvement in terms of prolonged survival time.

Improvement of the Antitumor Efficacy of Intratumoral Administration of Cucurbitacin Poly(Lactic-co-Glycolic Acid) Microspheres Incorporated in In Situ-Forming Sucrose Acetate Isobutyrate Depots

Localized drug delivery strategies for cancer therapy have been introduced for decades as a means of increasing drug concentration at tumor target site and minimizing systemic toxicities. In this paper, a combination of microspheres (MSs) and sucrose acetate isobutyrate (SAIB) in situ-forming implants (ISFIs) was evaluated for improving antitumor efficacy via intratumoral injection. Monodispersed cucurbitacin (Cuc)-loaded Poly (lactic-co-glycolic acid) (PLGA) MSs with mean diameter of about 5 μm were fabricated by Shirasu porous Glass (SPG) membrane emulsification technique, and their properties were investigated. The in vitro drug release pattern, antimelanoma efficiency, and drug distribution in tumor of three different intratumoral injection systems, that is, MSs, SAIB ISFIs, and combination of MSs and SAIB ISFIs (SAIB-MSs), was investigated. The Cuc-loaded MSs prepared by PLGA (LA/GA = 50:50, inherent viscosity = 0.87 dL/g), has an appropriate release pattern with lower initial burst and delayed drug release. SAIB-MSs have a much slower drug release rate than that of MSs or SAIB ISFIs. SAIB-MSs showed the best antitumor efficacy in melanoma-bearing mice model, and the results of drug distribution in tumor revealed that the incorporation MSs in SAIB solution obviously extended the residence of drug in tumor. The low Cuc concentration in tumor periphery region after intratumoral administration of SAIB-MSs demonstrated poor drug penetration of this system. For further improving the antitumor efficacy of intratumoral chemotherapy, elegant designing to carriers with both extended residency and wide drug distribution in tumor is needed.

Abstract B90: Hapten enhanced personalized chemoimmunotherapy by ultra-minimum incision personalized intratumoral chemoimmuno-therapy: UMIPIC-therapy in advanced pancreatic cancer

Abstract Backgound: To evaluate the clinical effectiveness of hapten enhanced chemoimmunotherapy in the treatment of advanced pancreatic cancer by ultra-minimum incision personalized intratumoral chemoimmuno-Therapy (UMIPIC-Therapy) and to further analyze its role as an immune adjuvant. Method: Patients with late stage pancreatic cancer (92 cases) were treated with UMIPIC-Therapy or just intratumoral Chemotherapy (ITCT) , UMIPIC-Therapy is a proprietary therapeutic regimen which is composed of three components (i.e. an oxidant, a cytotoxic drug and a hapten) that is utilized in chemotherapeutic modulation. The patients (at end of study, 47 patients with complete response analysis data and 45 patients with complete survival data were in the randomly divided two groups: Control group of ITCT alone with an oxidant and a cytotoxic drug without hapten and the experimental group receiving UMIPIC-Therapy with an oxidant, a cytotoxic drug plus hapten. Result: In the ITCT (control) and UMIPIC (experimental) groups, the clinical response rates were 92.86% and 82.88% respectively; the median survival time and 6-month survival rate were 4.98 months vs 6.45 months and 45% vs 64%, respectively. While all of above mentioned showed no statistical difference (P&amp;gt;0.05), 1-year survival rate of the ITCT group was 5% while those of the ITCIT group was 28% and statistically significant (P&amp;lt;0.05). Conclusion: The hapten enhanced immunotherapy by ultra-minimum incision personalized intratuoral chemoimmuno-therapy (UMIPIC-Therapy) is shown to be effective in the pancreatic cancer. Our data suggests that the hapten plays an important role in prolonging the patient survival time is could be very valuable in future clinic applications. Citation Format: Baofa Yu, Feng Gao, Wei Han, Zhenlu Ma. Hapten enhanced personalized chemoimmunotherapy by ultra-minimum incision personalized intratumoral chemoimmuno-therapy: UMIPIC-therapy in advanced pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B90.

Hapten-enhanced overall survival time in advanced hepatocellular carcinoma by ultro-minimum incision personalized intratumoral chemoimmunotherapy.

PurposeTo compare the therapeutic effects of ultra-minimum incision personalized intratumoral chemoimmunotherapy (UMIPIC) with intratumoral chemotherapy (ITCT) in the treatment of advanced hepatocellular carcinomas and to analyze the effect of hapten as an immune booster.Materials and methodsPatients with advanced hepatocellular carcinomas were treated with UMIPIC or ITCT with the same therapeutic procedure; the UMIPIC method had a proprietary regimen including an oxidant, a cytotoxic drug, and hapten, while ITCT delivered the same drug excluding hapten. Of 339 patients in total, 119 of the UMIPIC patients (n=214) had response data and 214 had survival data, and of the ITCT patients (n=125), 61 had response data and 125 had survival data. Tumor response was assessed with a computed tomography scan 6–8 weeks after the initial treatment; the survival rate was evaluated by follow-up visits. Tumor size was classified as small (<5 cm), large (5–10 cm), or very large (>10 cm); tumor sizes with liver function categorized using Child–Pugh class (A and B) were analyzed by correlation with overall survival.ResultsThe response rates (complete response + partial response + stable disease) were 78.68% and 81.52% in the UMIPIC and ITCT groups, respectively, with no statistically significant difference; however, the median overall survival was 7 months for UMIPIC (test) and 4 months for ITCT (control), respectively (P<0.01). The 6-month and 1-year survival rates for UMIPIC and ITCT were 58.88% vs 32.3% and 30.37% vs 13.6%, respectively (P<0.01). Single and multiple UMIPIC revealed significant improvement in overall survival compared to that of ITCT. Child–Pugh class A patients had a longer duration of survival compared to Child–Pugh class B patients in UMIPIC therapy.ConclusionHapten had enhanced therapeutic effect with improvement in the survival duration in UMIPIC compared to ITCT. After reexamination, the response rate was not different due to inflammation caused by hapten. Hapten has been found to play an important role in immunotherapy to improve patient survival.

Hapten-enhanced therapeutic effect in advanced stages of lung cancer by ultra-minimum incision personalized intratumoral chemoimmunotherapy therapy.

AimThe objective of the study reported here was to evaluate the therapeutic effects of hapten-enhanced chemoimmunotherapy in the treatment of advanced lung cancer by ultra-minimum incision personalized intratumoral chemoimmunotherapy (UMIPIC) and to analyze the effect of this immune booster.Materials and methodsA total of 97 patients with advanced lung cancer were treated with UMIPIC or intratumoral chemotherapy (ITCT). UMIPIC was delivered intratumorally in combination with a proprietary therapeutic regimen composed of three components – an oxidant, a cytotoxic drug, and hapten. ITCT applied using the same procedures and regimen, only without hapten. All data from the two groups were reviewed and analyzed. A total of 55 patients were treated with UMIPIC and 42 with ITCT. Patient responses were assessed with computed tomography scan 4–6 weeks after treatment, and all of the patients were followed until their deaths.ResultsMedian overall survival was 11.23 months in the UMIPIC (test) group and 5.62 months in the ITCT (control) group (P<0.01). The 6-month and 1-year survival rates of the UMIPIC and ITCT groups were 76.36% versus 45.23% (P<0.01) and 45.45% versus 23.81% (P<0.05), respectively. Two cycles of UMIPIC treatment (n=19) conferred a significant survival benefit compared with two cycles of ITCT (n=29); significant benefits in survival time were also found with UMIPIC (n=20) compared with ITCT (n=13) when both were utilized without adjuvant treatment.ConclusionThe hapten-enhanced clinical effect of UMIPIC conferred a superior survival time in patients with advanced lung cancer compared with ITCT. The addition of the hapten in UMIPIC demonstrates a significant advantage in terms of prolonged survival time.

Enhancement of Intratumoral Chemotherapy with Cisplatin with or without Microwave Ablation and Lipiodol. Future Concept for Local Treatment in Lung Cancer.

Novel therapies for lung cancer are being explored nowadays with local therapies being the tip of the arrow. Intratumoral chemotherapy administration and local microwave ablation have been investigated in several studies. It has been previously proposed that lipiodol has the ability to modify the microenvironment matrix. In our current study we investigated this theory in BALBC mice. In total 160 BALBC mice were divided in eight groups: a) control, b) cisplatin, c) microwave, d) microwave and lipiodol, e) cisplatin and lipiodol, f) microwave and cisplatin, g) lipiodol and h) lipiodol, cisplatin and microwave. Lewis lung carcinoma cell lines (106) were injected into the right back leg of each mouse. After the 8th day, when the tumor volume was about 100mm3 the therapy application was initiated, once per week for four weeks. Magnetic resonance imaging was performed for each tumor when a mouse died or when sacrificed if they were still alive by the end of the experiment (8-Canal multifunctional spool; NORAS MRI products, Gmbh, Germany). Imaging and survival revealed efficient tumor apoptosis for the groups b,c,d,e and f. However; severe toxicity was observed in group h and no follow up was available for this group after the second week of therapy administration. Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect. Future modification of lipiodol might provide a more efficient method of therapy enhancement. Combination of drug and microwave ablation is possible and has an efficient apoptotic effect.

Platelet‐activating factor‐receptor in chemotherapy mediated acquired resistance of melanoma (LB495)

Pro‐oxidative stressors suppress host immunity via generating oxidized lipids with Platelet‐activating Factor‐receptor (PAF‐R) agonist activity. Since many chemotherapeutic agents are potent pro‐oxidative stressors, the present studies investigated if chemotherapy could thwart host anti‐tumor immunity against melanoma via PAF‐R activation. We demonstrate that treatment of melanoma cell lines and tumors with chemotherapeutic agents generates PAF‐R‐agonists. In a dual tumor model, we show that intratumoral chemotherapy with melphalan or etoposide of one tumor significantly augments the growth of other (untreated) tumor in wild‐type but not in PAF‐R‐deficient hosts. Chemotherapy‐mediated PAF‐R‐dependent increased tumor growth is blocked by systemic administration of antioxidants and cyclooxygenase‐2 (COX‐2) inhibitors. In addition, depleting antibodies against regulatory T cells (Tregs) significantly attenuated chemotherapy‐mediated enhanced tumor growth, suggesting the role of Tregs. Moreover, using FoxP3EGFP transgenic mice, we show that COX‐2 inhibitor blocked intratumoral Tregs, indicating that Tregs are downstream to COX‐2. Finally, PAF‐R agonists were identified in perfusates of melanoma patients undergoing isolated limb perfusion with melphalan chemotherapy. These findings provide evidence for a novel pathway by which PAF‐R agonists produced via chemotherapy modulate tumor growth via COX‐2‐Treg pathway. These studies explain some instances of chemotherapy treatment failure and provide potential therapeutic targets that could enhance the overall anti‐tumor effectiveness of chemotherapy.Grant Funding Source: NIH R01 HL062996, AICR 09A062, ACSIRG 4185607, Showalter Research Trust Fund 4485602

Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies

Strategies to enhance the already established doublet chemotherapy regimen for lung cancer have been investigated for more than 20 years. Initially, the concept was to administer chemotherapy drugs locally to the tumor site for efficient diffusion through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR) negative stage IIIa–IV International Union Against Cancer 7 (UICC-7), and with Eastern Cooperative Oncology Group (ECOG) 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%–1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin–based systemic chemotherapy in (higher) standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of intratumoral chemotherapy plus two cycles of low-dose intravenous chemotherapy according to our protocol. These encouraging results (even in very sick ECOG 2 patients with central obstructive non-small cell lung cancer having a worse prognosis and quality of life than a non-small cell lung cancer in ECOG 0 of the same tumor node metastasis [TNM]-stage without central obstruction) for a chemotherapy-only protocol that differs from conventional cisplatin-based doublet chemotherapy by the route, target site, and dose paves the way for broader applications of this technique. Finally, future perspectives of this treatment and pharmaceutical design for intratumoral administration are presented.

Dephosphorylation of D-peptide derivatives to form biofunctional, supramolecular nanofibers/hydrogels and their potential applications for intracellular imaging and intratumoral chemotherapy.

D-Peptides, as the enantiomers of the naturally occurring L-peptides, usually resist endogenous proteases and are presumably insensitive to most enzymes. But, it is unclear whether or how a phosphatase catalyzes the dephosphorylation from D-peptides. In this work, we examine the formation of the nanofibers of D-peptides via enzymatic dephosphorylation. By comparing the enzymatic hydrogelation of L-peptide and D-peptide based hydrogelators, we find that the chirality of the precursors of the hydrogelators affects little on the enzymatic hydrogelation resulted from the removal of the phosphate group from a tyrosine phosphate residue. The attachment of a therapeutic agent (e.g., taxol) or a fluorophore (e.g., 4-nitro-2,1,3-benzoxadiazole) to the D-peptide based hydrogelators affords a new type of biostable or biocompatible hydrogelators, which may find applications in intratumoral chemotherapy or intracellular imaging, respectively. This work, as the first comprehensive and systematic study of the unexpected enzymatic dephosphorylation of D-peptides, illustrates a useful approach to generate supramolecular hydrogels that have both biostability and other desired functions.

Randomized phase II trial of NGR-hTNF in combination with standard chemotherapy in previously untreated non-small cell lung cancer (NSCLC).

8035 Background: NGR-hTNF, a selective antivascular agent, induces at low dose an initial vascular normalization that greatly enhances the intratumoral chemotherapy uptake, with synergistic effects that were noted especially in combination with cisplatin and gemcitabine. Methods: Chemo-naive patients (pts) with advanced NSCLC were stratified by histology (nonsquamous or squamous) and PS (0 or 1) and randomly assigned to receive cisplatin 80 mg/m2/d1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) for 6 cycles, with (arm A) or without (arm B) NGR-hTNF given at 0.8 μg/m2/d1/q3w until progression. Progression-free survival (PFS) was primary aim (1-β=80%, 1-sided α=10%, n=102). Secondary aims comprised adverse events (AEs), response rate (RR), and overall survival (OS). Results: Baseline characteristics in arm A (n=62) vs B (n=59) were: median age: 62 vs 63 years; men: 37 vs 39; PS 1: 23 vs 23; squamous: 18 v 17; smokers: 41 vs 43. For the nonsquamous stratum, 299 cycles were given in arm A (mean 7.0; range 1-20) and 192 in arm B (4.8; 1-6), while for the squamous stratum, 113 in arm A (6.7; 1-31) and 52 in arm B (3.5; 1-6). Rates of grade 3/4 AEs were similar (arm A vs B): neutropenia 13% vs 18%, anaemia 7% vs 4% and fatigue 7% vs 11%. No grade 3/4 AEs related to NGR-hTNF or bleeding/pulmonary hemorrhage events were reported in the squamous subset. With median follow-up time of 24.2 months, median PFS (5.8 vs 5.6 months; HR=0.92), RR (25% vs 21%) and 1-year OS (53% vs 53%) were similar between the two treatment arms. However, by predefined analysis in the squamous stratum, median PFS was 5.6 months for arm A and 4.3 months for arm B (hazard ratio, HR=0.75) and median OS was 14.2 months for arm A and 9.7 months for arm B (HR=0.49; p=0.07). In pts with squamous histology, RR was 38% for arm A and 27% for arm B (odds ratio=1.6), while the median changes in tumor size on treatment from baseline to 2nd, 4th and 6th cycle for arm A vs B were -32% vs -20%, -41% vs -19%, and -42% vs -14%, respectively. Conclusions: Clinical tolerability and benefit were noted in squamous NSCLC with NGR-hTNF plus cisplatin and gemcitabine, which deserve further investigation. Clinical trial information: NCT00994097.

Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGR-hTNF given in combination with chemotherapy (CT).

3038 Background: Antitumor effects of NGR-hTNF (N), a tumor-targeted antivascular agent, are driven at low dose by an early vessel stabilization that greatly enhances both intratumoral CT uptake and T-cell infiltration. Synergism with CT was shown in immunocompetent mice, but not in nude mice lacking functional T cells. Methods: By an individual patient pooled analysis of 396 patients (pts) from 7 ph II trials in 6 tumor types, we estimated the effects of baseline PBLC on the antitumor activity of N (with or without CT) and CT alone. Low dose N (0.8 μg/m2) was given in combination with CT in 171 pts. Control groups of 140 and 85 pts receiving N and CT alone, respectively, were also analyzed. CT was doxorubicin or a platinum-based regimen. In all trials, response to therapy was assessed every 6 weeks by RECIST. Endpoints of interest were response rate (RR, complete plus partial response), disease control rate (DCR, RR plus stable disease), duration of response (DOR) and progression-free survival (PFS). In logistic and Cox regression analyses, PBLC data were dichotomized in high or low levels by the median cutpoint (1.5/mL; 95% CI, 1.4-1.6). Multivariate models included age, sex, PS and tumor type as covariates. Results: In both N-alone and CT-alone groups, there was no statistically significant difference in treatment effect according to baseline PBLC. Conversely, high PBLC were related to better treatment outcome in the N plus CT group, compared to low PBLC. In this N plus CT group, high PBLC (vs low) were associated with higher RR (OR=2.8; 95% CI, 1.2-6.3; p=.01) and DCR (OR=2.6; 1.3-4.9; p=.004), and with longer DOR (HR=0.39; 0.16-0.96; p=.04) and PFS (HR=0.60; 0.43-0.85; p=.004). For high vs low PBLC, RR was 29% vs 14%, DCR 76% vs 57%, median DOR 8.2 vs 6.3 months, and median PFS 5.0 vs 3.0 months, respectively. On multivariate analyses, high PBLC remained an independent predictor of increased RR (OR=2.7; p=.01) and DCR (OR=2.6; p=.005), and improved DOR (HR=0.36; p=.04) and PFS (HR=0.60; p=.005). Conclusions: Consistently with preclinical data, these results highlight the potential value of PBLC in predicting tumor response to NGR-hTNF in combination with CT, which merits further clinical validation Clinical trial information: NCT00994097-NCT00484432-NCT00484276-NCT00484211-NCT00483509-NCT00483080-NCT01358071.

Clinico-immunological response to intratumoral versus intravenous neoadjuvant chemotherapy in advanced pediatric solid malignancies

Background:There is minimal literature on the use of intralesional chemotherapy in the pediatric age group. We undertook this present study to evaluate the two modalities (intratumoral and intravenous) of giving chemotherapy in terms of toxicity of chemotherapy, hematological parameters, efficacy of chemotherapy in reduction in volume of the tumor as well as resectability of tumor with special emphasis on immunological parameters.Materials and Methods:Advanced cases of Wilms’ tumor and Neuroblastoma were included in the study. Intratumoral chemotherapy was given through 25 G spinal needle under aseptic precautions and ultrasound guidance in the same dose as in systemic chemotherapy. Intravenous group was given chemotherapy in the usual way. Reassessment was carried out after every course of chemotherapy.Results:Group A included 16 cases of Wilms’ tumor and 6 cases of neuroblastoma. In group B, there were 14 cases of Wilms’ tumor and 8 of neuroblastoma. Vomiting, diarrhea, mucositis, and thrombophlebitis were more common in the intravenous group (P<0.05). The fall in Immunoglobulin A, Immunogloblulin G, Immunoglobulin M, and T-cell rosetting was more common in the intravenous group (P<0.05). Seventy percent of patients had completely resectable tumor at the end of 6 doses of intratumoral chemotherapy as compared to 50% resectability in the intravenous group (P<0.05).Conclusion:Intratumoral chemotherapy, besides causing less of the adverse effects and increasing the resecability rate, also causes less suppression of the immune system. This may be offered as an alternative safe and effective modality of treatment for advanced solid tumors.