Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Death

Breast Neoplasms

Neoplasms, Second Primary

Breast Diseases

Skin Diseases

We will enroll women with a biopsy-proven diagnosis of early-stage breast cancer (T1 N0), not eligible for neo-adjuvant therapy, scheduled to breast surgery (mastectomy or nodulectomy), who have given the informed consent for the study.

We will recruit 20 women who will undergo cryoablation.

The results will be compared with those obtained from a control group of 20 women, who will follow the same therapeutic pathway for the treatment of breast cancer without performing cryoablation.

cryoablation of breast cancer smaller than 2 cm

cryoablation

Federica Pediconi, MD

The aim of our study is to examine the cryoimmunologic response and its mechanisms induced by US-guided cryoablation of small breast tumors (\<2 cm) not eligible to neoadjuvant therapy. We will recruit 30 women who will undergo cryoablation and their results will be compared with a control group of 30 women, who will follow the same therapeutic pathway without performing cryoablation. All recruited patients will undergo an enrollment check, pre-cryoablation breast MRI and blood test to assess immune response, breast cancer US-guided cryoablation, post-cryoablation breast MRI and the same blood test to evaluate immunologic response. Within 21 days all patients will undergo breast surgery, with immuno-histopathological analysis on surgical specimen.

At least 10 days after surgery the patient will undergo clinical breast examination, blood test to assess immune response and patient satisfaction questionnaire.

Cryoablation treatment will be performed using a 14G cryoprobe under us-guidance for visualization of the ice ball surrounding the lesion. The ultrasound guide is used to ensure that the action affects the entire tumor and that therapeutic temperatures are reached in every part of the tumor.

Pre- and post- cryoablation breast MRI will be performed on a 3T magnet to assess cryoablation rate of success. Artificial intelligence algorithms will also be used for this purpose. Cryoablation treatment efficacy will also be evaluated with ultrasound.

The immunological fitness of cancer patients will be studied by flow cytometry, evaluating the presence of cytokines/chemokines relevant during anticancer immune response/tumor progression and for the presence of molecules released by cells during an immunogenic cell death.

The goal of our study will be to demonstrate that cryoablation of breast cancer can induce an antitumor immune response.

Therefore this approach could become an additional tool in the oncological treatment of breast cancer.

We will enroll women with a biopsy-proven diagnosis of early-stage breast cancer (T1 N0), not eligible for neo-adjuvant therapy, scheduled to breast surgery (mastectomy or nodulectomy), who have given informed consent for the study.

We will recruit 30 women who will undergo cryoablation. Their results will be compared with those obtained from a control group of 30 women, who will follow the same therapeutic pathway for the treatment of breast cancer without performing cryoablation.

The primary objective of our study is the characterization of the Immunogenic Cell Death (ICD) induced, the inflammatory response and the modulation of circulating T immune cells induced by tumor cryoablation treatment in the serum of breast cancer patients.

The circulating ICD biomarkers HMGB1, calreticulin and HSP70/90 will be analysed and also the profile of Th1 and Th2 type cytokines (IFN-γ, IL-12 (p40/p70), IL-15, IL-17, IL-2, IL-7, IP-10, IL-13, IL-5, IL-4), pro-inflammatory cytokines (IL-1α, IL-1β, IL- 6, TNF-α, IL-1RA, IL-2R, IL-8, CRP, IL-17, IFN-α), immunosuppressive cytokines (TGF-β1, IL-10, PGE2), chemokines (CCL5/RANTES, CCL3/MIP-1α, CCL4/MIP-1β, CCL2/MCP-1, CXCL9/MIG, CCL11/Eotaxin). Immune cell subsets will be characterized by flow cytometry: besides the conventional immune cell subsets (NK, Monocyte, Granulocyte, T and B cells), specific T cell subsets (Treg, naïve, memory, central effector) will be characterized and also the expression of immune markers associated to activation (CD137) or suppression/exhaustion (PD1, CTLA4, TIM3, LAG3).

Secondary endpoints are:

1. Cryoablation treatment efficacy and safety

   We will evaluate Recist criteria rate of complete response to cryoablation with breast ultrasound and breast MRI. Incidence vand severity of complications related to cryoablation will be monitored to establish safety profile ablating breast cancer with 10 mm margins around the primary tumor.
2. Cryoablation treatment capability to induce immunogenic tumor cell death.

   The presence and the extent of tumor necrosis / apoptosis on surgical specimen sections stained with hematoxylin-eosin will be evaluated. Immunohistochemical tests will be used to verify the activation of apoptotic mechanisms and Immunogenic cell death activation.
3. Tumor microvesicles release following Cryoablation treatment. During cell death, microvesicles (MVs) released by the cell transport a complex molecular cargo that can act as source of antigen repertoire and activatory signals to Antigen Presenting cells (APCs). Tumor derived MVs released in the serum of the patients will be isolated by ultracentrifugation steps as preliously described. The isolated MVs will be tested for the expression of Calreticulin and HMGB1.

All enrolled patients will undergo series of check as shown below (ICE-STUDY STEPS) :

enrollment check (STEP 0), breast MRI pre-cryoablation treatment (STEP 1) and post-cryoablation treatment (STEP 4), breast cancer US-guided cryoablation

(STEP 2), blood test to assess immune response (STEP 1, STEP 3, STEP 4, SURGERY and STEP 5) and surgical specimen immuno-histopathological analysis.

Enrollment check (STEP 0) will be conducted by a radiologist and an oncologist, where the patient's medical history will be collected and a breast examination of the affected site will be performed. The patient will also undergo breast US to evaluate cryoablation treatment feasibility (distance \>1 cm between the tumor and the skin, the nipple or the chest wall). If the patient is considered eligible to the study, the protocol will be illustrated in detail and informed consent will be collected.

Breast MRI will be performed pre-cryoablation (STEP 1) and post-cryoablation (STEP 4) to assess Visual-ICE ablation rate of success. Artificial intelligence algorithms will also be used for this purpose. Cryoablation treatment efficacy will also beevaluated with ultrasound (STEP 4).

STEP 2 consists in US-guided cryoablation treatment of the breast lesion.

Within 21 days from the enrollment the patient will undergo breast surgery and blood test.

During the Final STEP, the patient will undergo clinical breast examination, blood test to assess immune response and patient satisfaction questionnaire.

ICE-STUDY STEPS:

STEP 0: enrollment check

* Imaging: US
* Assessment:

  1. consent
  2. breast biopsy with histological result
  3. clinical history
  4. laboratory results
  5. clinical breast examination
  6. pharmacological therapy

STEP 1: Within 10 days from STEP 0

* Imaging: MRI (pre-cryoablation treatment)
* Assessment:

  1. blood test for immune response
  2. side effects

     STEP 2: CRYOABLATION (At least 24h after MRI)
* Assessment:

  1. cryoablation complications and side effects

     STEP 3: Blood test for immune response (48/72 h after cryoablation)

STEP 4: After 7 days from cryoablation and before surgery

* Imaging: MRI and/or US (post-cryoablation treatment)
* Assessment:

  1. patient satisfaction questionnaire.
  2. Side effects
  3. pharmacological therapy
  4. clinical breast examination
  5. blood test for immune response

SURGERY: Within 21 days from STEP 0

* Assessment:

  1. surgery
  2. complications
  3. specimen histological evaluation
  4. blood test for immune response

     STEP 5 - FINAL: At least 10 days after surgery
* Assessment:

  1. patient satisfaction questionnaire
  2. side effects
  3. pharmacological therapy
  4. clinical breast examination
  5. blood test for immune response

All cryoablation sessions will be performed under US-guidance by a single board-certi¿ed interventional radiologist. Biopsy, percutaneous cryoablation will be carried out using an argon-based cryoablation unit (BTG Cryoablation System).

Both preoperative US and MRI images will be compared in order to determine the correct positioning of the probe for tumor ablation. All the procedures will be carried out under local anesthesia given by injection of 2-5mL of 2% lidocaine proximal to the tumor lesion and along the course of the cryoprobes. One or more cryoprobes will be inserted into the targeted tumor using US guidance, through a small skin incision of 1-2mm. To avoid cryoinduced skin injury and facilitate the ablation of breast tissue at least 1cm beyond all apparent tumor margins, warming bags will be placed on the breast skin.

Due the relatively low heat load of breast parenchyma compared with internal organs, it was estimated that 1cm of visible ice beyond all the tumor margins would be necessary to generate cytotoxic temperatures (e.g.,-40¿C) throughout the breast tumor.

Each cryoablation treatment session consists in two cycles of 8 minutes of duration, followed by a 4-minute active thawing phase and a 4-minute passive thawing phase. The latter is considered useful to maximize cell death. US guidance will be also used to verify the formation of a homogeneous hypoechoic area, owing to the iceball, which encompassed the tumor all around and to detect early complications. The probes will be removed after the second phase of thawing, without the need for skin suture. After the procedure, the patients will be discharged in 2 hours a¿er the ablation, without any prescription.

The clinical outcome will be evaluated with US at the end of the cryoablation procedure and 7 days a¿er with clinical examination and MRI. The absence of such signs or symptoms will be interpreted as an optimal clinical result.

Immunogenic CELL DEATH and Inflammatory circulating Biomarkers will be analysed at different time points (5 time points:

before, 48 h and 7 days after cryoablation; before and after 10 days from surgery). Plasma will be isolated by EDTA treated blood (10 ml/sample) by centrifugation (4000 rmp/5'/4°C) and aliquoted and stored at -80°C.

The ICD biomarkers characterized will be: calreticulin, HMGB1, HSP70/90 (by ELISA and/or chemioluminescence immune sandwich tests).

Circulating Inflammatory mediators will also be analyzed by xMAP Multiplex platform including the following molecules:

Th1 and Th2 type cytokines (IFN-γ, IL-12 (p40/p70), IL-15, IL-17, IL-2, IL-7, IP-10, IL-13, IL-5, IL-4), pro-inflammatory

cytokines (IL-1α, IL-1β, IL-6, TNF-α, IL-1RA, IL-2R, IL-8, CRP, IL-17, IFN-α), immunosuppressive cytokines (TGF-β1, IL- 10, PGE2), chemokines (CCL5/RANTES, CCL3/MIP-1α, CCL4/MIP-1β, CCL2/MCP-1, CXCL9/MIG, CCL11/Eotaxin)\] will be analyzed.

The samples of each patient will be analysed for each biomarker simultaneously to avoid inter-experiment bias.

Microvesicles will be isolated by ultracentrifugation steps in micro-method scale (2 mL of plasma) and the analysis of calreticulin and HMGB1 will be performed by flow cytometry/ELISA (3 Time point: before, 48h and at the end of the procedure) Immune phenotyping will be performed by mulitparametric flow cytometry, characterizing the immune cell subsets(NK, T, B cells, granulocyte, monocytes). T cell subsets will be specifically characterized for Treg (CD25/foxp3), Naive/memory effector memory T cell (CCR7/CD45RA) and for activatory or exhausted phenotype (CD137, ICOS, PD1, CTLA4, TIM3, LAG3).

To Detect Cryoimmunologic Response Induced by Early Breast Cancer Ultrasound-guided Cryoablation (ICE-study)

Early Breast Cancer Ultrasound-guided Visual-ICE Galil Cryoablation; Can Tumor Cell Death Induced by Cryoablation be Detected by Specific Circulating Markers?

Characterization of the Immunogenic Cell Death induced by tumor cryoablation treatment in the serum of breast cancer patients.

Evaluation of serum modifications of the following molecules:

Th1 and Th2 type cytokines (IFN-γ, IL-12 (p40/p70), IL-15, IL-17, IL-2, IL-7, IP-10, IL-13, IL-5, IL-4)

Characterization of the Immunogenic Cell Death induced by tumor cryoablation treatment in the serum of breast cancer patients.

Evaluation of serum modifications of the following molecules:

pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α, IL-1RA, IL-2R, IL-8, CRP, IL-17, IFN-α),

Characterization of the Immunogenic Cell Death induced by tumor cryoablation treatment in the serum of breast cancer patients.

Evaluation of serum modifications of the following molecules:

immunosuppressive cytokines (TGF-β1, IL-10, PGE2),

Characterization of the Immunogenic Cell Death induced by tumor cryoablation treatment in the serum of breast cancer patients.

Evaluation of serum modifications of the following molecules:

chemokines (CCL5/RANTES, CCL3/MIP-1α, CCL4/MIP-1β, CCL2/MCP-1, CXCL9/MIG, CCL11/Eotaxin),

Characterization of the Immunogenic Cell Death induced by tumor cryoablation treatment in the serum of breast cancer patients.

Evaluation of serum modifications of the following molecules: ATP and HMGB1 are molecules released in the serum by cancer cells during immunogenic cell death.

Evaluate Recist criteria rate of complete response to cryoablation with breast ultrasound and breast MRI

Analyzing surgical specimen sections stained with hematoxylin-eosin, the presence and the extent of tumor (cm) necrosis will be evaluated.

ablating breast cancer with 5-10 mm margins around the primary tumor.

University of Roma La Sapienza

Prof. Federica Pediconi

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Wen-Fang Cheng, MD, PhD

Cervical cancer is the most frequent neoplasm of women in Taiwan and in the world. It influences about 2,700 women with about 1,000 women dying of cervical cancer each year and in Taiwan. Human papillomaviruses (HPV) have been consistently implicated in causing cervical cancer especially those high-risk types which have been strongly associated with cervical cancer. In recent years, there has been compelling evidence that infection with human papillomavirus (HPV) is a major etiologic factor in the development of cervical intraepithelial neoplasia (CIN) and cervical carcinoma.

As in most virus-induced diseases, an adequate immune response is likely to play a key role in the clearance of HPV infections and HPV-related lesions. This assumption is born out by both epidemiological studies and animal models. Immune-compromised patients such as HIV-infected women, organ transplant recipients, and patients suffering from other forms of malignancies, are at a higher risk of developing CIN lesions and invasive cervical cancer. Moreover, several studies establish the existence of natural HPV E7-specific cytotoxic T lymphocyte (CTL) immunity in humans. Only a minority of women infected with oncogenic HPV types develop CIN or cervical cancer. Indeed, the majority of CIN lesions do not progress or even regress to normal cytology, indicating that other factors such as an inadequate immune function are necessary for the development of progressive CIN lesions and cervical carcinoma.

Consequently, the HLA class I and II phenotypes may be correlated with an effective immune response against HPV-associated cervical lesions. Differences in the recognition of foreign antigens, such as those contributed by alleles at the HLA class I or II loci, might be proposed to affect the risk of developing cervical cancer.

In the present proposal, the investigators would like to examine the HLA class I and II associations among Taiwanese women with cervical neoplasia. The purposes of this proposal are:

1. to address the relationships between the HLA class I and II haplotype, HPV infection, and cervical cancer; and
2. to elucidate the immunologic responses to HPV type 16 in different HLA class I and II haplotypes. It will help the investigators to identify which population of HLA genotypes is more susceptible to HPV infection and progresses to invasive cervical cancer. The results of this research will be very useful for the prevention and screening of cervical cancer in the future.

1. To survey the incidence of HPV infection in CIN and cervical cancer patients.

   Using epidemiologic data drawn from a wide range of countries and population groups, investigators have found evidence of HPV in 90% to 95% of cervical cancers. The incidence of HPV in cervical cancer was 79% in our own report. Besides, 91% of high-grade CIN cases and 50% of low-grade CIN cases could be attributed to HPV infection in Taiwanese women. Because these reports for Taiwanese women were published around 10 years ago, it is important to survey and update the incidence of HPV in CIN and cervical cancer patients in Taiwanese women. We will survey the incidence of HPV infection in 500 cervical cancer patients, 100 patients of CIN and 100 normal population patients.
2. To survey the human leukocyte antigen haplotype in CIN and cervical cancer patients.

   HLA class I and II alleles have been reported to associate with the nasopharyngeal carcinoma in Taiwan. Besides, human leukocyte antigen class I and II alleles might interplay in the response to interferon-alpha treatment in Taiwanese patients with chronic hepatitis C virus infection. We will detect the HLA class I and II haplotype first and then correlate them with the CIN and cervical cancer patients.
3. To identify the correlation between HLA class I and II haplotype and HPV infection and CIN and cervical cancer.

   We will further survey the correlation between HLA class I and II and the genotypes of HPV in CIN and cervical cancer patients. We will identify which HLA class I and II haplotypes have positive or negative correlation with HPV infection, CIN and cervical cancer. Then we would determine which specific HLA antigens are important in determining the risk of HPV infection, CIN and cervical cancer.
4. To elucidate the immunologic responses to HPV type 16 in HLA2 with different II haplotypes and the role of immunogenetics in the carcinogenesis of cervical cancer.

HPV type 16 has been identified to be the highest incidence of malignant HPV genotypes in cervical cancer. Our laboratory has set up immunologic assays for evaluating the immune responses to HPV type 16. We will survey the immune response to HPV type 16 in those HLA class I and II haplotypes which have positive or negative correlation with the HPV infection and cervical cancer. We would identify which population of HLA genotype are more susceptible to HPV infection and invasive cervical cancer and elucidate the role of immunogenetics in the HPV infection and carcinogenesis of cervical cancer.

The Correlation Between the Haplotype of Human Leukocyte Antigen (HLA) and Human Papillomavirus

National Taiwan University Hospital

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Interleukin-2

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Patients that received prior interleukin 2 (IL-2) therapy will receive a myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day x 2 days intravenous (IV)), fludarabine (25mg/m\^2/day IV X 5 days) and 1200 cGy total body irradiation (TBI). Following the lymphodepleting regimen, patient will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum 3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses).

Patients that have not received prior interleukin 2 (IL-2) therapy will receive a myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day x 2 days intravenous (IV)), fludarabine (25mg/m\^2/day IV X 5 days) and 1200 cGy total body irradiation (TBI). Following the lymphodepleting regimen, patient will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum 3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses)

Melanoma Reactive TIL

720,000 IU/kg/dose every 8 hours for up to 15 doses

IL-2

1200 total body irradiation (TBI)

Steven A Rosenberg, M.D.

Background:

* In a study in humans with melanoma, patients given total body irradiation to suppress the immune system in conjunction with chemotherapy showed a significant clinical response.
* In previous studies, about one-half of patients given tumor-fighting cells (cells created from the patient's tumor cells and grown in the laboratory) showed some anti-tumor response.

Objective: To determine whether tumor-fighting cells taken from a melanoma tumor and grown in the lab can more effectively at fight melanoma when the patient's immune system is suppressed and cannot attack them.

Eligibility: Patients 18 years of age or older with metastatic melanoma who have tumor reactive cells available.

Design:

-Patients are assigned to one of two groups - those having received prior therapy with Interleukin-2 (IL-2) and those who have not.

After five days of injections of filgrastim, a medicine to stimulated the growth of white blood cells, patients undergo apheresis or bone marrow harvesting, or both, to collect stem cells for later re-infusion. For apheresis, whole blood is collected through a needle in an arm vein and circulated through a cell-separating machine where the stem cells are extracted. The rest of the blood is returned through the same needle or a needle in the other arm. Bone marrow harvesting is done under general anesthesia. Stem cells are collected through a large needle inserted into the hipbone.-Patients' immune system cells and bone marrow function are eliminated with chemotherapy (7 days) and total body irradiation (3 days) so the patient's immune system cells will not fight the tumor-fighting cells they are given in treatment.

* 1 to 3 days after total body irradiation, patients receive the tumor-fighting cells by intravenous (IV) infusion. After the cells are infused, they receive interleukin-2 (IL-2) infusions every 8 hours for 5 days.
* 2 days after infusion of the tumor-fighting cells, patients receive the stem cells collected earlier by apheresis.
* Patients are evaluated 4 to 6 weeks after cell infusion to look for tumor response to treatment. Patients whose tumor has not grown return to the National Institutes of Health (NIH) every 1 to 3 months for blood tests, scans and x-rays.

Background:

The use of immunosuppression prior to adoptive transfer of lymphocytes from tumor bearing mice was based on a variety of murine models demonstrating improved therapeutic effectiveness of the adoptive transfer of lymphocytes following immunosuppression of the host.

Because the degree of immunosuppression has been highly correlated with the ability to eliminate large tumors in murine models, we have been conducting a clinical trial, 04-C-0288, in which 200cGy of total body irradiation is used in conjunction with the same cyclophosphamide and fludarabine regimen used in our prior adoptive cell therapy trials which have demonstrated significant clinical responses.

We have measured T-regulatory cells in patients participating in 04-C-0288 and have demonstrated that despite the addition of 200cGy total body irradiation (TBI), T-regulatory cells promptly reconstituted in the host. Complete clinical responses have not been significantly improved over other adoptive cell therapy regimens.

Thus, in this trial we would like to more adequately test our hypothesis that more intensive lymphodepletion will increase complete responses and persistence of the transferred cells.

Objective:

To determine whether tumor reactive lymphocytes infused in conjunction with the administration of high-dose IL-2 in patients who have received prior therapy with IL-2 and those who have not may result in complete clinical tumor regression in patients with metastatic melanoma receiving a myeloablative lymphoid depleting preparative regimen.

To evaluate the safety of the treatment in patients receiving the myeloablative conditioning regimen, cell transfer and IL-2.

To determine the survival in patients, of infused cells following the administration of the myeloablative regimen, using analysis of the sequence of the variable region of the T cell receptor or flow cytometry (FACS).

Eligibility:

Patients who are greater than or equal to 18 years of age who have tumor reactive cells available, with metastatic melanoma, and are physically able to tolerate high-dose IL-2.

Design:

Patients will be assigned to one of two cohorts, those having received prior therapy with IL-2 and those who have not.

Patients will receive a myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day x 2 days IV), fludarabine (25mg/m\^2/day IV X 5 days) and 1200 cGy total body irradiation (TBI).

Patients will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum 3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses).

On day 1 of patients will receive intravenous administration of cryopreserved autologous CD34+ cells.

A complete evaluation of evaluable lesions will be conducted 4-6 weeks after cell infusion. Patients will be enrolled into two strata, using a phase II optimal design to rule out a modest CR rate of 24%, with 33-54 patients enrolled in each strata.

Chemotherapy, Irradiation, Cell Infusions, and Interleukin-2 to Treat Metastatic Melanoma

Phase II Study Using a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy and Intensive Total Body Irradiation Followed by Infusion of Tumor Reactive Lymphocytes and Reconstitution With CD34+ Stem Cells in Metastatic Melanoma

Determine if the combination of high dose aldesleukin, reinfused cells after lymphocyte depleting chemotherapy and 1200 cGy total body irradiation (TBI) is able to be associated with a modest fraction of patients with metastatic melanoma who can experience a complete response to therapy.

Complete response (CR) is a disappearance of all target lesions.

Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

National Cancer Institute (NCI)

Steven A. Rosenberg, M.D./National Cancer Institute

TBI 1200 cGy + TIL +HD IL-2, Prior IL-2

TBI 1200 cGy + TIL +HD IL-2, no Prior IL-2

Total

Age, Categorical

Age Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Steven A. Rosenberg, M.D.

Complete Response

Number of Participants With Adverse Events

Overall Study

Melanoma, Cutaneous Malignant

Imiquimod

Monatide (IMS 3015)

Immunomodulating Agents

Adjuvants, Immunologic

Interferons

gp100:209-217(210M) peptide emulsified in MONTANIDE ISA-51 or Montanide ISA 51 VG injected subcutaneously on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks).

gp100:209-217(210M) peptide emulsified in MONTANIDE ISA-51 or Montanide ISA 51 VG injected subcutaneously on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks); following the injection patients will apply imiquimod to the skin at the site of injection daily for 5 days.

gp100:209-217(210M) in 0.9% Sodium Chloride Injection injected intradermally on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks).

gp100:209-217(210M) peptide in 0.9% Sodium Chloride Injection injected intradermally on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks); following the injection patients will apply imiquimod to the skin at the site of the injection daily for 5 days.

gp100:209-217(210M) peptide emulsified in Montanide ISA 51 VG injected subcutaneously on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks).

gp100:209-217(210M) peptide emulsified in Montanide ISA 51 VG injected subcutaneously on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks); following the injection patients will apply imiquimod to the skin at the site of injection daily for 5 days.

gp100:209-217 (210M)

Montanide ISA-51

Apply imiquimod 5% cream to the skin at the site of injection daily for 5 days

This study will evaluate the immunization effects of a vaccine for patients who are at risk for recurrence of their skin cancer. That is, the risk of cancer is higher if melanoma has invaded deep into the skin or lymph nodes. Currently, the only therapy that the U.S. Food and Drug Administration (FDA) has approved for preventing recurrence of melanoma is alpha-interferon. But the research data are controversial. In this study, the vaccine to be used, called gp100, contains a piece of a protein called a peptide, which melanoma cancer cells produce.

Patients 16 and older who have had confirmed melanoma surgically removed and whose tissue type is tested as being human leukocyte antigen serotype within HLA-A serotype group (HLA-A2), through a specific blood test, may be eligible for this study.

Up to 132 participants will be enrolled. There will be a physical examination and collection of blood samples for tests, and making sure that x-rays and scans are current. Patients will be randomly assigned to four groups. Group 1 will receive the peptide with an adjuvant (assistant) oil-based liquid called Montanide ISA-51, as an injection in the thigh. Group 2 will receive gp100, Montanide, and a cream called imiquimod, which the FDA has approved for treating genital warts and herpes but that may help immune cells in the skin to recognize the vaccine. Imiquimod will be applied to the skin for 5 days. Group 3 will receive gp100 mixed in salt water given as several mini-doses under the skin of the thigh. Group 4 will also receive several mini-doses of gp100 mixed in saline, as well as imiquimod cream applied to the skin for 5 days. All patients will receive the gp100 every 3 weeks for 12 weeks. Every dose is a cycle, with four cycles considered a course of therapy. If the melanoma does not return or patients do not experience side effects from this therapy, then the courses of vaccine will repeated for up to 12 cycles of therapy (3 courses over 33 weeks). Side effects of the peptide vaccination include local swelling, swelling of local lymph nodes, bruising, and pain and redness at the injection sites. There may be chills or fever. Patients will be watched closely for such side effects.

To study how the vaccine changes the action of cells in the immune system, patients' white blood cells (lymphocytes) will be obtained, involving a separate informed consent. The procedure, called leukaphersis, requires inserting a needle into the arm, to obtain blood going into a machine, which divides the blood into red cells, plasma (or the serum part), and lymphocytes. The lymphocytes are removed, and the plasma and red cells returned to the patient through a second needle in the other arm. Risks associated with the procedure include fainting, which can be prevented by patients' eating before coming to the lab, and bleeding and infection at the needle site. Patients will undergo leukapheresis will be done about four times: before receiving the vaccine, 3 weeks after the first four doses, and then after 8 cycles and 12 cycles. Patients assigned to the groups receiving imiquimod will be asked to record every time they apply that cream and describe any symptoms developed during the study. All patients will be watched closely for any sign that their melanoma has returned. Before and throughout the study, multiple blood tests will be conducted.

The vaccine, Montanide, and imiquimod may increase patients' immune system in fighting off new tumors, but that is not known now. However, the study may provide information that will be useful in treating melanoma patients in the future.

Background:

A previous clinical trial has been conducted in the Surgery Branch National Cancer Institute (NCI) in which gp100 immunizations have been administered to patients with melanoma in the adjuvant setting. In this prior protocol, the peptide emulsified in Incomplete Freund's Adjuvant was administered subcutaneously using several different schedules and was well tolerated except for mild and transient erythema at the site of injection. Each of the schedules provided successful immunization although the q3w schedule was the best tolerated locally and three courses of immunization appeared to be sufficient using this regimen. An important finding from the adjuvant protocol however was the significant increase in immune precursors specifically reactive against peptide and tumor that occurred with increasing courses of immunization. These findings have encouraged us to now further explore the optimal methods for generating immune precursors using the gp100:209-217(210M) peptide by testing the impact of an additional immune adjuvant, imiquimod, reported to increase the immunizing potential of antigens as well as evaluate an alternate route of injection, intradermal administration.

Objectives:

The primary objective of this trial is to evaluate the immunologic activity of immunization with four different preparations of the gp100:209-217(210M) melanoma antigen peptide and potentially select one for further study.

Eligibility:

HLA-A 0201 patients, age greater than or equal 16 years, with primary melanomas with lesions that are ulcerated and greater than or equal 2mm, or any lesions that are greater than or equal 4.0 mm in thickness, or greater than or equal 1 positive lymph node, or local recurrence, or resected metastatic disease, within 6 months of surgical resection will be considered. Patients who have ocular or mucosal melanoma or who require systemic steroid therapy will be excluded. The following patients will also be excluded: have previously been immunized with gp100; have known hypersensitivity to any of the agents used in this study; have previously received chemotherapy for treatment of melanoma; or who are undergoing or have undergone in the past 3 weeks any systemic therapy except surgery for their cancer.

Design:

Patients will be randomized into one of the following four arms:

1. gp100:209-217(210M) peptide emulsified in MONTANIDE ISA-51 or Montanide ISA 51 VG injected subcutaneously on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks).
2. gp100:209-217(210M) peptide emulsified in MONTANIDE ISA-51 or Montanide ISA 51 VG injected subcutaneously on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks); following the injection patients will apply imiquimod to the skin at the site of injection daily for 5 days.
3. gp100:209-217(210M) in 0.9% Sodium Chloride Injection injected intradermally on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks).
4. gp100:209-217(210M) peptide in 0.9% Sodium Chloride Injection injected intradermally on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks); following the injection patients will apply imiquimod to the skin at the site of the injection daily for 5 days.

Immunizations will be administered on an outpatient basis unless side effects or the patient's clinical condition warrants hospitalization. Patients will receive full clinical evaluation three weeks after 8 cycles and 12 cycles.

Each of the arms will be conducted using a two-stage optimal design Since the primary objective is to select one regimen from among the four on the basis of the immune response, this design allows there to be greater than 80% probability of correctly selecting the superior arm if there is either a tie in the number of immune responses, or if there is at least one more immune response on one arm than the other three arms, and if the true response rates are 15%, 15%, 15% and 35%. Initially, 19 patients will be enrolled in each arm and evaluated; if 0 to 3 of 19 in an arm have an immune response to T2 cells pulsed with 0.01 M peptide after the 4th, 8th, and 12th cycles, no further patients would be randomized to receive the peptide on that arm. If at least four immunologic responses are noted after the 8th cycle, then accrual to 33 patients would take place. If all four arms need to be completed and 33 patients need to be completed in each arm, a total of 132 patients are required.

Evaluation of the Impact of Adjuvants Accompanying Peptide Immunization in High-Risk Melanoma

Evaluation of the Impact of Adjuvants Accompanying Peptide Immunization in High Risk Melanoma

Comparison of six different preparations of the gp100:209-217 (210M) melanoma antigen peptide. The arm with the greater number of immunologic responses will be the one most likely to be selected for future study on the basis of immunization alone. Evidence of immunization consist of at least 10 Elispots/100,000 cells above background. An injection site reaction is not an immune response.

Here are the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

Dr. Steven Rosenberg

Adj-3 A2 gp209(2M) in IFA SQ (Vortex)

Adj-3 A2 gp209(2M) in IFA SQ + Imiquimod (Vortex)

Adj-3 A2 gp209(2M) in Saline ID

Adj-3 A2 gp209(2M) in Saline ID + Imiquimod

Adj-3 A2 gp209(2M) in IFA SQ (2 Syringe)

Adj-3 A2 gp209(2M) in IFA SQ + Imiquimod (2 Syringe)

American Indian or Alaskan Natives

Asian or Pacific Islander

Native Hawaiian

Black of non-Hispanic Origin

Hispanic

White of non-Hispanic Origin

Other or Unknown

Race/Ethnicity, Customized

The number of participants analyzed and results are correct. We do not have the immunologic response rate data for all patients.

Immunologic Response Rate

Recurrence

polysaccharide-K

Analgesics, Non-Narcotic

Anti-Bacterial Agents

Antibiotics, Antitubercular

Protective Agents

Radiation-Protective Agents

melanoma antigen recognized by T-cells (MART)-1:27-35 peptide every three weeks for four cycles (Arm I).

High-dose (HD) bolus interleukin-2 (IL-2) (720,000 IU/kg every 8 hours for up to 12 doses) after enrollment on Arm I (Arm IA)

27-35(27L):melanoma antigen recognized by T-cells (MART)-1 peptide every three weeks for four cycles (Arm II).

High-dose (HD) bolus interleukin-2 (IL-2) (720,000 IU/kg every 8 hours for up to 12 doses) after enrollment on Arm II (Arm IIA)

melanoma antigen recognized by T-cells (MART)-1:26-35(27L) peptide every three weeks for four cycles (Arm III).

High-dose (HD) bolus interleukin-2 (IL-2) (720,000 IU/kg every 8 hours for up to 12 doses) after enrollment on Arm III (Arm IIIA)

27-35(27L):melanoma antigen recognized by T-cells (MART)-1 peptide plus the gp100:209-217(210M) peptide emulsified together every three weeks for four cycles (Arm IV).

High-dose (HD) bolus interleukin-2 (IL-2) (720,000 IU/kg every 8 hours for up to 12 doses) after enrollment on Arm IV (Arm IVA)

Glycoprotein 100 (GP100): 209-217 (210M)

720,000 IU/kg as an intravenous bolus over a 15 minute period every 8 hours and continuing for up to 4 days (a maximum of 12 doses).

Interleukin-2 (IL-2)

Montanide ISA 51

Melanoma antigen recognized by T-cells (MART)-1: 27-35

27-35 (27L): melanoma antigen recognized by T-cells (MART)-1

melanoma antigen recognized by T-cells (MART)-1: 26-35(27L)

This study will examine the effectiveness and side effects of an experimental vaccine to prevent recurrence of melanoma. The likelihood of melanoma returning is higher in patients who have melanoma lesions deep in the skin, in patients who have had positive lymph nodes, and in patients who have had surgery for metastatic disease (cancer that has spread beyond the primary site). Melanoma tumors produce proteins called glycoprotein 100 (gp100) and melanoma-associated antigen recognized by T cells 1 (MART-1). Vaccination with specific pieces of these proteins (peptides) may boost the immune system's fight against the cancer. The vaccine injections are mixed with an oil-based substance called Montanide ISA-51, which is intended to increase the immune response to the peptide.

Patients 16 years of age and older whose melanoma has been surgically removed and who are currently free of disease may be eligible for this study. Candidates will be screened with a physical examination and blood and urine tests. An electrocardiogram (EKG), x-rays and other imaging studies will be done if recent results are not available. Some candidates may require heart tests, such as a cardiac stress test or echocardiogram, or lung function tests. In addition, all candidates will be tested for human leukocyte antigen (HLA) tissue type; patients must be type human leukocyte antigens (HLA-A)\*0201, the type on which this vaccine is based.

Participants will be randomly assigned to receive one of four different vaccines to determine which peptides offer the best immunity. Each treatment course consists of two injections of the vaccines every 3 weeks for four times. The injections are given under the skin of the thigh. After every other treatment course (every 6 months), patients will undergo a series of x-rays and scans to look for tumor. The immunizations may continue for up to 12 months as long as the melanoma does not return. The injections are given at the National Institutes of Health (NIH) Clinical Center. Patients are monitored for 1 hour after each injection and have blood tests and a physical examination to look for treatment side effects.

Patients will be followed with blood tests every 12 weeks to monitor body functions. They will also undergo leukapheresis-a procedure to collect white blood cells-before starting treatment and about 3 to 4 weeks after the fourth vaccine to evaluate how the vaccines affect the action of the immune system cells. For this procedure, blood is drawn through a needle in the arm, similar to donating blood. The blood goes through a machine that separates out the lymphocytes (white blood cells), and the rest of the blood is returned through a needle in the other arm. Some patients may undergo a biopsy-surgical removal of a small piece of tissue under local anesthetic-of normal skin and tumor or lymph node tissue to examine the effects of the vaccines on the tumor immune cells.

Patients whose disease returns during the first course of vaccine therapy will have surgery to remove the tumor and will continue to receive the vaccine treatment. Patients whose tumor returns after completing one course of therapy may receive a substance called interleukin-2 (IL-2), which can boost immune function against the tumor. interleukin-2 (IL-2) is given intravenously (through a small tube placed in a vein) every 8 hours for 4 days. This regimen is repeated after 10 to 14 days. Those who respond to interleukin-2 (IL-2) will have a third course of treatment after 2 months. Patients whose disease recurs after treatment will be taken off the study and will be referred back to their referring physician or to another study, if an appropriate one is available.

Human leukocyte antigens (HLA-A)\*0201 positive patients at high risk for recurrence of melanoma, or completely resected metastatic melanoma will receive immunization with peptides representing human leukocyte antigen (HLA)-restricted T cell epitopes of the melanoma antigen recognized by T-cells (MART-1) or glycoprotein 100 (gp100) melanoma antigens emulsified in Montanide ISA-51 or Montanide trademark(TM) ISA 51 vegetable grade (VG). Patients will be randomized to receive one of three different melanoma antigen recognized by T-cells (MART-1) peptides or to receive a combination of a melanoma antigen recognized by T-cells (MART-1) peptide plus a glycoprotein 100 (gp100) peptide. This study is designed to evaluate the immunologic effects of the different peptide immunizations.

Peptide Vaccination for Patients at High Risk for Recurrent Melanoma

Randomized Comparison of Peptide Immunization in Patients at High Risk for Recurrence of Melanoma

Immunologic monitoring will be conducted using in vitro sensitization assays. The immunologic response in these assays will be considered positive if at least a two-fold increase in vaccine specific interferon gamma (y-IFN) secretion is seen between post vaccination specimens compared to the pre vaccination specimens.

Response is measured from the time measurement criteria are first met for complete response (CR) or partial response (PR) (whichever is first) until the first date that recurrent disease is objectively documented. Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Here are the number of participants with adverse events. For details about the adverse events see the adverse event module.

Adj-2 MART-1: 27-35

Adj-2 HD IL-2 After MART-1: 27-35

Adj-2 27-35 (27L) MART-1 (Mod9mer) Peptide Q3wks x 4

Adj-2 HD IL-2 After 27-35 (27L): MART-1 (Mod9mer)

Adj-2 MART-1: 26-35 (27L) (Mod10mer) Peptide Q3wks x 4

Adj-2 HD IL-2 After MART-1: 26-35 (27L) (Mod10mer)

Adj-2 27-35 (27L): MART-1 + gp100: 209-217 (210M) Q3wks x 4

Adj-2 HD IL-2 After 27-35 (27L): MART-1 + gp209-2M

The number of participants analyzed and results are correct. We do not have the response rate data for all patients.

Response Rate

Antibodies

Antibodies, Monoclonal

Molgramostim

Sargramostim

Tin Fluorides

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

GM-CSF will be administered subcutaneously daily for 14 days in a dose of 125 µg/m2 beginning on D1 of each 21-day cycle for 8 cycles until month 6. Maintenance therapy will begin at month 6 and will consist 14 days of GM-CSF repeated every 3 months for up to 2 years or until disease progression, whichever occurs first.

Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)

Patients will be treated with 4 courses of ipilimumab administered every 3 weeks intravenously in a dose of 10 mg/kg, with appropriate stopping/de-escalation rules. Maintenance therapy will begin at month 6 and will consist of ipilimumab in the same dose administered at the end of cycle 4 repeated every 3 months for up to 2 years or until disease progression, whichever occurs first.

Lynn E. Spitler, M.D.

The study is an open-label, single arm single Center Phase II study to evaluate the safety and efficacy of the combination of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF, Leukine) and Ipilimumab (Yervoy) as therapy for patients with unresectable metastatic malignant melanoma.

The study is an open-label, single arm single Center Phase II study to evaluate the safety and efficacy of the combination of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF, Leukine) and Ipilimumab (Yervoy) as therapy for patients with unresectable metastatic malignant melanoma. The patient sample will be approximately 43 evaluable individuals, males and females 18 years of age or older with measurable metastatic melanoma. Immunologic testing will be done to evaluate correlation with clinical outcome.

Patients will be treated with 4 courses of GM-CSF and ipilimumab administered every 3 weeks. GM-CSF will be administered subcutaneously daily for 14 days in a dose of 125 µg/m2 beginning on D1 of each 21-day cycle. Ipilimumab intravenously in a dose of 10 mg/kg, with appropriate stopping/de-escalation rules. After the initial 3 months (4 cycles) of treatment, GM-CSF administration will continue for 4 additional cycles on the same schedule and dose without ipilimumab for 14 days every 21 days until month 6. Maintenance therapy will begin at month 6 and will consist of ipilimumab in the same dose administered at the end of cycle 4 combined with 14 days of GM-CSF. Administration of this combination will be repeated every 3 months for up to 2 years or until disease progression, whichever occurs first. During the maintenance phase, GM-CSF will only be administered for 14 days in conjunction with ipilimumab and will not be administered in the intervening time period.

Granulocyte Macrophage-Colony Stimulating Factor and Ipilimumab as Therapy in Melanoma

GM-CSF and Ipilimumab as Therapy in Metastatic Melanoma, a Phase II Study

Disease control rate will be measured at 24 weeks from the start date of protocol therapy using the immune-related Response Criteria (irRC)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
To Detect Cryoimmunologic Response Induced by Early Breast Cancer Ultrasound-guided Cryoablation (ICE-study)	NCT05727813	Cancer, Treatme... Tumor of Breast Systemic Inflam... Stage I Breast ...	cryoablation	18 Years -	University of Roma La Sapienza
The Correlation Between the Haplotype of Human Leukocyte Antigen (HLA) and Human Papillomavirus	NCT00154479	Cancer of Cervi...		18 Years - 80 Years	National Taiwan University Hospital
Chemotherapy, Irradiation, Cell Infusions, and Interleukin-2 to Treat Metastatic Melanoma	NCT00314106	Metastatic Mela...	Melanoma Reacti... Cyclophosphamid... IL-2 Fludarabine 1200 total body...	18 Years -	National Institutes of Health Clinical Center (CC)
Evaluation of the Impact of Adjuvants Accompanying Peptide Immunization in High-Risk Melanoma	NCT00273910	High-Risk Melan...	gp100:209-217 (... Montanide ISA-5... Imiquimod	7 Years -	National Institutes of Health Clinical Center (CC)
Evaluation of the Impact of Adjuvants Accompanying Peptide Immunization in High-Risk Melanoma	NCT00273910	High-Risk Melan...	gp100:209-217 (... Montanide ISA-5... Imiquimod	7 Years -	National Institutes of Health Clinical Center (CC)
Peptide Vaccination for Patients at High Risk for Recurrent Melanoma	NCT00059475	Melanoma	Glycoprotein 10... Interleukin-2 (... Montanide ISA 5... Melanoma antige... 27-35 (27L): me... melanoma antige...	7 Years -	National Institutes of Health Clinical Center (CC)
Chemotherapy, Irradiation, Cell Infusions, and Interleukin-2 to Treat Metastatic Melanoma	NCT00314106	Metastatic Mela...	Melanoma Reacti... Cyclophosphamid... IL-2 Fludarabine 1200 total body...	18 Years -	National Institutes of Health Clinical Center (CC)
Granulocyte Macrophage-Colony Stimulating Factor and Ipilimumab as Therapy in Melanoma	NCT01363206	Malignant Melan...	Granulocyte-Mac... Ipilimumab	18 Years -	Northern California Melanoma Center
Granulocyte Macrophage-Colony Stimulating Factor and Ipilimumab as Therapy in Melanoma	NCT01363206	Malignant Melan...	Granulocyte-Mac... Ipilimumab	18 Years -	Northern California Melanoma Center

Spots Global Cancer Trial Database for immunologic response