Complete Regression Of Primary Tumor Research Articles

Accurately Controlled Tumor Temperature with Silica-Coated Gold Nanorods for Optimal Immune Checkpoint Blockade Therapy.

Photothermal therapy (PTT) at mild temperatures ranging from 44 to 45 °C holds tremendous promise as a strategy for inducing potent immunogenic cell death (ICD) within tumor tissues, which can reverse the immunosuppressive tumor microenvironment (ITM) into an immune-responsive milieu. However, accurately and precisely controlling the tumor temperature remains a formidable challenge. Here, we report the precision photothermal immunotherapy by using silica-coated gold nanorods (AuNR@SiO2), and investigating the optimal administration routes and treatment protocols, which enabled to achieve the sustained and controlled mild heating within the tumor tissues. First, the highest photothermal performance of AuNR@SiO2 with 20-nm silica shell thickness than 5 or 40 nm was confirmed invitro and invivo. Then, the optimal conditions for precision immunotherapy were further investigated to produce mild temperature (44 to 45 °C) accurately in tumor tissues. The optimal conditions with AuNR@SiO2 result in a distinct cell death with high early/late apoptosis and low necrosis, leading to very efficient ICD compared to lower or higher temperatures. In colon tumor-bearing mice, intratumorally injected AuNR@SiO2 efficiently promotes a mild temperature within the tumor tissues by local irradiation of near-infrared (NIR) laser. This mild PTT substantially increases the population of mature dendritic cells (DCs) and cytotoxic T cells (CTLs) within tumor tissues, ultimately reversing the ITM into an immune-responsive milieu. Furthermore, we found that the combination mild PTT with AuNR@SiO2 and anti-PD-L1 therapy could lead to the 100% complete regression of primary tumors and immunological memory to prevent tumor recurrence. Collectively, this study demonstrates that AuNR@SiO2 with a robust methodology capable of continuously inducing mild temperature accurately within the ITM holds promise as an approach to achieve the precision photothermal immunotherapy.

Light-triggered polymeric prodrug and nano-assembly for chemo-photodynamic therapy and potentiate immune checkpoint blockade immunotherapy for hepatocellular carcinoma

Immune checkpoint blockade (ICB) therapy has emerged as a promising approach for the treatment of hepatocellular carcinoma (HCC), especially for advanced and metastatic tumors. However, many HCC patients do not respond due to low tumor antigen exposure and the highly immunosuppressive tumor microenvironment (ITM). Chemotherapy and photodynamic therapy are considered to be effective methods for eliciting anti-tumor immune responses. Here, we developed a light-triggered nanoplatform Ce6@PMTKP for combination chemo-photodynamic therapy and the potentiation of ICB therapy. The Ce6@PMTKP micelles entrapped Ce6 for photodynamic therapy, while PMTKP contains the ROS-sensitive paclitaxel (PTX) polymeric prodrug for chemotherapy. The Ce6@PMTKP micelles showed excellent tumor accumulation and light-triggered drug release. Compared with chemotherapy or photodynamic therapy alone, the combination therapy mediated by Ce6@PMTKP was found to be more effective in the elimination of tumors, induction of immunogenic cell death, and the promotion of dendritic cell maturation and cytotoxic T lymphocytes infiltration, thus mitigating ITM immunosuppression. When combined with anti-PD-L1 immunotherapy, the Ce6@PMTKP micelles induced complete regression of primary tumors and effectively inhibited distant metastatic tumors by enhancing anti-tumor immune responses.

Herpesvirus-Mimicking DNAzyme-Loaded Nanoparticles as a Mitochondrial DNA Stress Inducer to Activate Innate Immunity for Tumor Therapy.

Virus-based immunotherapy is a promising approach to treat tumor. Closely mimicking the structure and sequential infection processes of natural viruses is highly desirable for effective tumor immunotherapy but remains challenging. Here, inspired by the robust innate immunity induced by herpesvirus, a herpesvirus-mimicking nanoparticle (named Vir-ZM@TD) is engineered for tumor therapy by mimicking the structure and infection processes of herpesvirus. In this biomimetic system, DNAzyme-loaded manganese-doped zeolitic imidazolate framework-90 (ZIF-90) nanoparticles (ZM@TD) mimic the virus nucleocapsid containing the genome; the erythrocyte membrane mimics the viral envelope; and two functional peptides, RGD and HA2 peptides, resemble the surface glycoprotein spikes of herpesvirus. Vir-ZM@TD can both effectively evade rapid clearance in the blood circulation and closely mimic the serial infection processes of herpesvirus, including specific tumor targeting, membrane fusion-mediated endosomal escape, and TFAM (transcription factor A, mitochondrial) deficiency-triggered mitochondrial DNA stress, as well as the release of manganese ions (Mn2+ ) from organelles into the cytosol, ultimately effectively priming cGAS-STING pathway-mediated innate immunity with 68% complete regression of primary tumors and extending by 32 days the median survival time of 4T1-tumor-bearing mice.

Complete regression of primary melanoma associated with nevi involution under BRAF inhibitors: A case report and review of the literature.

Melanoma is one of the most immunogenic tumors among human neoplasms, with numerous clinical observations of partial or completely regressed tumors. It is an aggressive tumor, with the greatest reported number of somatic mutations, BRAF mutation being the most common one. BRAF mutation is also present in a higher percentage in benign nevi. Complete regression of primary tumor and involution of nevi are, however, rare phenomenon in melanoma that can appear in relation with UV exposure, surgical trauma, target therapy in melanoma, pregnancy or host immune response to an evolving melanoma tumor. We present the case of a 58-year-old man with a completely regressed metastatic melanoma who developed a second melanoma with concomitant involution of papillomatous nevi under BRAF inhibitors treatment. In reviewed literature we have found 53 cases of completely regressed primary melanomas, neither of them reporting nevi involution. Complete regression of primary tumor can occur as an immune response to tumor progression. Nevi can involute under BRAF inhibitor therapy, but development of new malignant lesions under BRAF inhibitors is linked to BRAF wild-type. Documentation of primary tumor and dynamic changes in nevi highlight the need of a good clinical skin examination and increase the utility of baseline and sequential dermoscopy in melanoma.

Multifunctional Tumor-Targeted Polymer-Peptide-Drug Delivery System for Treatment of Primary and Metastatic Cancers

In order to improve drug delivery to drug-resistant ovarian tumors, we constructed a multifunctional polymer-peptide-drug conjugate (PPDC) system for effective treatment of primary and metastatic ovarian cancers. The PPDC consists of the poly(Ethylene Glycol) (PEG) polymeric carrier conjugated via citric acid spacers to anticancer drug (Camptothecin, CPT), tumor targeting moiety (LRHR, a synthetic analog of luteinizing hormone-releasing hormone) and a suppressor of cellular antiapoptotic defense (BH3 peptide). To test the conjugates in vitro and in vivo, cancer cells were isolated from tissue samples obtained from patients with ovarian primary tumor and metastatic malignant ascites. It was found that cells isolated from malignant ascites were more aggressive in terms of tumor growth and more resistant to chemotherapy when compared with those isolated from primary tumors. PPDC containing two copies of drugs and peptides was most efficient in treatment of primary tumors and intraperitoneal metastases. Multiple treatments with this PPDC led to almost complete regression of primary tumor and prevented growth of malignant ascites. The proposed multifunctional polymeric delivery system which consists of multiple copies of the drug and peptides demonstrated significantly higher antitumor activity in primary and metastatic cancers when compared with drug alone and PEG-CPT conjugate.

Dipeptidyl Peptidase Inhibition Accelerates Dendritic Cell Cross Priming of Tumor-Reactive T Cells Resulting in Regression of Established Tumors

BACKGROUND: PT-100 is an aminoboronic dipeptide that competitively inhibits dipeptidyl peptidases. While PT-100 has no direct effect on tumor cells in vitro, it exhibits potent antitumor effects in vivo. We have shown that female C57BL/6 (B6) mice with MB49 tumors, which naturally express the male minor histocompatibility antigen complex (HY), are primed to HY, but the immune response is insufficient to control tumor growth. In this study, we used the well-characterized HY antigen system to examine the immunomodulatory effects of PT-100 during treatment-induced tumor regression.METHODS: B6 female mice were inoculated subcutaneously with MB49 (106 cells) on day 0 and treated daily with PT-100 by gavage. For re-challenge experiments mice received high dose MB49 (3×106 cells) three weeks after complete regression of primary tumors. IFN-g ELISPOT was used to measure HY antigen specific T cell responses in the spleen and lymph nodes (LNs) during tumor growth. For adoptive transfer experiments, T cells were magnetic-bead purified from LNs and spleens of tumor-bearing PT-100 treated, tumor-bearing sham treated, or naïve mice and injected intravenously into Rag1−/− recipients (1.2×106 cells) which were then inoculated with high dose MB49. T cells were depleted with monoclonal antibodies to CD4 and CD8. Dendritic cells (DCs) were depleted with diphtheria toxin (DT) in bone marrow chimeras expressing the DT receptor under the CD11c promoter. DC activation examined by flow cytometry. For vaccine experiments, HY-expressing DCs were cultured from male B6 bone marrow and injected intraperitoneally (1×105 cells).RESULTS: PT-100 treatment resulted in complete regression of MB49, even when limited to the first week (days 3–7) during tumor progression. Treatment started later than week 1 was insufficient to establish consistent, complete tumor regression. High-dose re-challenge of PT-100 treated mice resulted in initial growth followed by regression without additional PT-100. IFN-gELISPOT revealed a robust response against HY in spleens of controls on day 17. Interestingly, PT-100 treated mice had quantitatively similar priming, but the response peaked earlier (day 10), just prior to tumor regression. Purified T cells from PT-100 treated donors collected on day 17 mediated markedly enhanced tumor protection compared to recipients of T cells from sham treated tumor-bearing mice despite significantly more HY-reactive cells in the spleen and LNs of sham treated-tumor bearing mice by that time. T cell or DC depletion independently abrogated the anti-tumor effect of PT-100 and treatment with PT-100 increased CD80 and CD86 expression on LN DC populations in vivo. Although HY DC vaccination does not affect tumor growth, supplementation of the DC vaccine with PT-100 mediated a therapeutic effect resulting in regression of well-established tumors.CONCLUSIONS: PT-100 establishes a consistent and potent antitumor effect against MB49 dependent on T cells and DCs. Treatment results in a memory response that is protective against high dose MB49 re-challenge. PT-100-induced tumor regression is associated with enhanced early tumor priming, associated with increases in activated DCs. T cells from PT-100 treated mice elicit superior protection upon adoptive transfer compared to shams, despite quantitatively less tumor-primed T cells, suggesting the PT-100 antitumor effect may involve a qualitative difference in T cell function. PT-100 given as an adjuvant to a DC vaccine results in increased potency and regression of established tumors. Inhibition of dipeptidyl peptidases modulate naturally occurring anti-tumor immune responses and contribute to the generation of a therapeutic anti-cancer vaccine.

Preliminary Results of Re-irradiation for Locally Recurrent Nasopharyngeal Carcinoma with Intensity Modulated Radiotherapy

To evaluate the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). From March 2005 to March 2007, 39 patients with locally recurrent NPC received re-irradiation using IMRT. The rT classification distribution was 7 for rT1, 10 for rT2, 13 for rT3, and 9 for r T4. Median time from first course of radiotherapy to re-irradiation was 38 months. The median prescribed dose was 66.7 Gy (range, 54-72.1 Gy) with 2-2.3 Gy per fractionation. Two patients received 16 Gy brachytherapy boost in 2 fractions. Twenty-nine patients received cisplatin-based induction or adjuvant chemotherapy. Median follow-up time was 14 months (range, 4-29 months). After re-irradiation, 64.5% of patients had complete regression of primary tumor. One-year loco-regional progression-free, distant metastasis-free and overall survival rates were 96.6, 88.5, and 69.3%, respectively. One patient developed recurrence in the nasopharynx. Four patients developed metastases at a distant site: one in the bone and liver, one in the lung, one in the liver and one in the bone. Acute toxicity (skin, mucosa, and xerostomia) was acceptable according to the Radiation Therapy Oncology Group criteria. The necrosis was seen after the end of IMRT in 8 patients with bleeding. The fractional dose is 2.3Gy in five patients of them. Our preliminary results showed that good control can be achieved using IMRT . As high dose/ fractional dose IMRT can result in radio-necrosis of nasopharyngeal mucosa, the prescription dose/fractional dose should be suitably decreased. More patients and longer term follow-up are warranted to evaluate late toxicity and treatment outcome

Optimal time interval between capecitabine intake and radiotherapy in preoperative chemoradiation for locally advanced rectal cancer

Capecitabine and its metabolites reach peak plasma concentrations 1 to 2 hours after a single oral administration, and concentrations rapidly decrease thereafter. We performed a retrospective analysis to find the optimal time interval between capecitabine administration and radiotherapy for rectal cancer. The time interval between capecitabine intake and radiotherapy was measured in patients who were treated with preoperative radiotherapy and concurrent capecitabine for rectal cancer. Patients were classified into the following groups. Group A1 included patients who took capecitabine 1 hour before radiotherapy, and Group B1 included all other patients. Group B1 was then subdivided into Group A2 (patients who took capecitabine 2 hours before radiotherapy) and Group B2. Group B2 was further divided into Group A3 and Group B3 with the same method. Total mesorectal excision was performed 6 weeks after completion of chemoradiation and the pathologic response was evaluated. A total of 200 patients were enrolled in this study. Pathologic examination showed that Group A1 had higher rates of complete regression of primary tumors in the rectum (23.5% vs. 9.6%, p = 0.01), good response (44.7% vs. 25.2%, p = 0.006), and lower T stages (p = 0.021) compared with Group B1; however, Groups A2 and A3 did not show any improvement compared with Groups B2 and B3. Multivariate analysis showed that increases in primary tumors in the rectum and good response were only significant when capecitabine was administered 1 hour before radiotherapy. In preoperative chemoradiotherapy for rectal cancer, the pathologic response could be improved by administering capecitabine 1 hour before radiotherapy.

Neoplastic Mesorectal Microfoci (MMF) following Neoadjuvant Chemoradiotherapy: Clinical and Prognostic Implications

Neoplastic microfoci have frequently been found in the mesorectum, with poor outcome. In this study, incidence and clinical significance of mesorectal microfoci (MMF) were analyzed in patients operated on for rectal cancer following neoadjuvant chemoradiation. A case series of 68 patients with extraperitoneal rectal cancer treated with neoadjuvant chemoradiation and surgery (including total mesorectal excision) were investigated for presence of neoplastic MMF. MMF were found in 26 cases (38.2%). Increasing incidence of microfoci was statistically related to pathologic involvement of the bowel wall (P = 0.0006), Mandard's tumor regression grading (P = 0.0006), and pathologic neoplastic mesorectal involvement (P < 0.00001). None of the nine patients with complete tumor disappearance displayed both microfoci and lymph node metastasis. Only one local recurrence developed in a patient with multiple MMF. One out of nine pT0 or TRG1 patients (11.1%) had distant metastases compared with 15 out of 59 pT1-4 or TRG2-5 (25.4%, P = 0.70). A remarkable incidence of MMF was found following chemoradiation. However, when this therapy induced complete regression of primary tumor (pT0-TRG1), we found that node metastases and neoplastic MMF also disappeared. These features should be confirmed to assess the impact of these microfoci in treatment decision making in rectal cancers.

Neoplastic Mesorectal Microfoci (MMF) Following Neoadjuvant Chemoradiotherapy: Clinical and Prognostic Implications

Neoplastic microfoci have frequently been found in the mesorectum, with poor outcome. In this study, incidence and clinical significance of mesorectal microfoci (MMF) were analyzed in patients operated upon for rectal cancer following neoadjuvant chemoradiation. A case series of 68 patients with extraperitoneal rectal cancer, treated with neoadjuvant chemoradiation and surgery (including total mesorectal excision), was investigated for the presence of neoplastic MMF. Mesorectal microfoci were found in 26 cases (38.2%). Increasing incidence of microfoci was statistically related to pathologic involvement of bowel wall (P = 0.0006), Mandard's tumor regression grading (P = 0.0006) and pathologic neoplastic mesorectal involvement (P < 0.00001). None of the nine patients with complete tumor disappearance displayed both microfoci and lymph node metastasis. Only one local recurrence developed in a patient with multiple MMF. Out of 9 pT0 or TRG1 patients, 1 (11.1%) had distant metastases, compared to 15 out of 59 pT1-4 or TRG2-5 (25.4%, P = 0.70). A remarkable incidence of MMF was found following chemoradiation. However, when this therapy induces complete regression of primary tumor (pT0-TRG1), node metastases and neoplastic MMF could also disappear, as shown in our cases. These features should be confirmed because they could significantly impact the treatment decision-making of rectal cancers.

IL-12 + GM-CSF Microsphere Therapy Induces Eradication of Advanced Spontaneous Tumors in her-2/neu Transgenic Mice But Fails to Achieve Long-Term Cure Due to the Inability to Maintain Effector T-Cell Activity

A single intratumoral injection of interleukin-12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres induced the regression of advanced spontaneous mammary tumors, suppressed additional tumor development, and enhanced survival in her-2/neu transgenic mice. Posttherapy tumor eradication was dependent on both CD4+ and CD8+ T cells and correlated with the tumor infiltration kinetics of a transient effector T-cell response. Upon long-term monitoring, tumor regression was found to be temporary, and disease-free survival was not achieved despite the development of systemic anti-tumor cytotoxic T-cell memory and antibody responses. Repeated immunization of mice enhanced short-term tumor suppression, resulting in the complete regression of primary tumors in up to 40% of the mice, but did not improve long-term survival owing to recurrence. The failure of chronic therapy to achieve complete cure was associated with an inability to maintain the intensity of the posttherapy effector T-cell response in this model.

Reirradiation of nasopharyngeal carcinoma withintensity-modulated radiotherapy

Background and purpose To evaluate the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). Materials and methods Between October 2001 and May 2004, 31 patients with locally recurrent NPC received reirradiation using IMRT. The rT classification distribution was 3 for rT1, 5 for rT2, 9 for rT3, and 14 for rT4. Median time from first course of radiotherapy to reirradiation was 51 months. IMRT was performed using step-and-shoot method with nine 4–6 MV photon fields and median prescribed dose was 54 Gy (range: 50–60 Gy). Additional treatments included cisplatin-based induction chemotherapy in 68% and radiosurgery boost with a single dose which ranged from 8.5 to 12.5 Gy in 32%. Median follow-up time was 11 months. Results After reirradiation, 58% of patients had complete regression of primary tumor. One-year loco-regional progression-free, distant metastasis-free and overall survival rates were 56, 90, and 63%, respectively. Significantly better 1-year local progression-free rate was observed in rT1–3 than rT4 tumor (100 vs. 35%). Grade 3 late toxicities, mostly ototoxicity/cranial neuropathy, occurred in six patients (19%). One-year actuarial rates of late toxicities were 70% for all grades and 25% for Grade 3. Conclusion Our preliminary results showed that good control of rT1–3 NPC can be achieved using IMRT with a dose between 50 and 60 Gy, whereas the outcome for rT4 tumor remained poor. Late toxicities were common but incidence of severe toxicities was relatively low.