Cancer-oocyte SAS1B protein is expressed at the cell surface of multiple solid tumors and targeted with antibody-drug conjugates.

Background: perm crosomal LLPinding (SAS1B) protein is found in oocytes, which is necessary for sperm-oocyte interaction, and also in uterine and pancreatic cancers. Anti-SAS1B antibody-drug conjugates (ADCs) arrested growth in these cancers. However, SAS1B expression in cancers and normal tissues has not been characterized.

Intratumoral IFN-γ or topical TLR7 agonist promotes infiltration of melanoma metastases by T lymphocytes expanded in the blood after cancer vaccine.

Background: Immune-mediated melanoma regression relies on melanoma-reactive T cells infiltrating tumor. Cancer vaccines increase circulating melanoma-reactive T cells, but little is known about vaccine-induced circulating lymphocytes (viCLs) homing to tumor or whether interventions are needed to enhance infiltration. We hypothesized that viCLs infiltrate melanoma metastases, and intratumoral interferon (IFN)-γ or Toll-like receptor 7 (TLR7) agonism enhances infiltration.

A nano-enhanced vaccine for metastatic melanoma immunotherapy.

: Despite the huge advancements in cancer therapies and treatments over the past decade, most patients with metastasized melanoma still die from the disease. This poor prognosis largely results from resistance to conventional chemotherapies and other cytotoxic drugs. We have previously identified 6 antigenic peptides derived from melanomas that have proven efficacious for activating CD4 T cells in clinical trials for melanoma.

Phase I/II clinical trial of a helper peptide vaccine plus PD-1 blockade in PD-1 antibody-naïve and PD-1 antibody-experienced patients with melanoma (MEL64).

Background: A vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe, immunogenic, and clinically active. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus programmed death 1 (PD-1) blockade.

Participants And Methods: Participants with advanced melanoma received 6MHP vaccines in an incomplete Freund's adjuvant (6 vaccines over 12 weeks).

An activation to memory differentiation trajectory of tumor-infiltrating lymphocytes informs metastatic melanoma outcomes.

There is a need for better classification and understanding of tumor-infiltrating lymphocytes (TILs). Here, we applied advanced functional genomics to interrogate 9,000 human tumors and multiple single-cell sequencing sets using benchmarked T cell states, comprehensive T cell differentiation trajectories, human and mouse vaccine responses, and other human TILs. Compared with other T cell states, enrichment of T memory/resident memory programs was observed across solid tumors.

A pilot trial of vaccination with Carcinoembryonic antigen and Her2/neu peptides in advanced colorectal cancer.

Checkpoint-blockade therapy (CBT) is approved for select colorectal cancer (CRC) patents, but additional immunotherapeutic options are needed. We hypothesized that vaccination with carcinoembryonic antigen (CEA) and Her2/neu (Her2) peptides would be immunogenic and well tolerated by participants with advanced CRC. A pilot clinical trial (NCT00091286) was conducted in HLA-A2 or -A3 Stage IIIC-IV CRC patients.

Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund's adjuvant (IFA) for resected high-risk melanoma.

Background: We performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund's adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone.

Methods: Participants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8 T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC.

Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist.

Background: Experimental cancer vaccines are traditionally administered by injection in subcutaneous tissue or muscle, commonly with adjuvants that create chronic inflammatory depots. Injection of melanoma-derived peptides induces T cell responses; however, the depots that form following injection may inhibit optimization of the immune response. In skin, epidermal Langerhans cells (LC) are a dominant source of professional antigen presenting cells.

A phase 1 study of NY-ESO-1 vaccine + anti-CTLA4 antibody Ipilimumab (IPI) in patients with unresectable or metastatic melanoma.

Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1 tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC.

Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund's adjuvant, cyclophosphamide, and polyICLC (Mel63).

Background: Peptide vaccines designed to stimulate melanoma-reactive CD4 T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund's adjuvant (IFA) would be safe and would support strong, durable CD4 T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.

Formation and phenotypic characterization of CD49a, CD49b and CD103 expressing CD8 T cell populations in human metastatic melanoma.

Integrins α1β1 (CD49a), α2β1 (CD49b) and αEβ7 (CD103) mediate retention of lymphocytes in peripheral tissues, and their expression is upregulated on tumor infiltrating lymphocytes (TIL) compared to circulating lymphocytes. Little is known about what induces expression of these retention integrins (RI) nor whether RI define subsets in the tumor microenvironment (TME) with a specific phenotype. Human metastatic melanoma-derived CD8 TIL could be grouped into five subpopulations based on RI expression patterns: RI, CD49a only, CD49aCD49b, CD49aCD103, or positive for all three RI.

Evaluation of SAS1B as a target for antibody-drug conjugate therapy in the treatment of pancreatic cancer.

Successful therapeutic options remain elusive for pancreatic cancer. The exquisite sensitivity and specificity of humoral and cellular immunity may provide therapeutic approaches if antigens specific for pancreatic cancer cells can be identified. Here we characterize SAS1B (ovastacin, , astacin-like), a cancer-oocyte antigen, as an attractive immunotoxin target expressed at the surface of human pancreatic cancer cells, with limited expression among normal tissues.

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer.

Background: Breast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date.

Vaccine-draining lymph nodes of cancer patients for generating anti-cancer antibodies.

Background: Our research is focused on using the vaccine draining lymph node to better understand the immune response to cancer vaccines and as a possible source of anti-cancer reagents. We evaluated vaccine draining lymph nodes archived from a clinical study in melanoma patients and determined the reaction of B cells to the vaccine peptides.

Methods: Mononuclear cells (MNCs) were recovered from cryopreserved lymph nodes that were directly receiving drainage from multi-peptide melanoma vaccine.

Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases.

Introduction: Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases.

Patients And Methods: Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily.

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases.

Introduction: Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases.

A randomized pilot trial testing the safety and immunologic effects of a MAGE-A3 protein plus AS15 immunostimulant administered into muscle or into dermal/subcutaneous sites.

Introduction: Methods to induce T cell responses to protein vaccines have not been optimized. The immunostimulant AS15 has been administered with the recombinant MAGE-A3 protein (recMAGE-A3) i.m.

Vaccination with Melanoma Helper Peptides Induces Antibody Responses Associated with Improved Overall Survival.

Purpose: A melanoma vaccine incorporating six peptides designed to induce helper T-cell responses to melanoma antigens has induced Th1-dominant CD4(+) T-cell responses in most patients, and induced durable clinical responses or stable disease in 24% of evaluable patients. The present study tested whether this vaccine also induced antibody (Ab) responses to each peptide, and whether Ab responses were associated with T-cell responses and with clinical outcome.

Experimental Design: Serum samples were studied from 35 patients with stage III-IV melanomas vaccinated with 6 melanoma helper peptides (6MHP).

TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10.

Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cell infiltration of metastases. However, most tumors lack significant immune infiltration prior to therapy. Selected chemokines promote T-cell migration into tumors; thus, agents that induce these chemokines in the tumor microenvironment (TME) may improve responses to systemic immune therapy.

A melanoma helper peptide vaccine increases Th1 cytokine production by leukocytes in peripheral blood and immunized lymph nodes.

Background: Cancers produce soluble and cell-associated molecules that can suppress or alter antitumor immunity. Preclinical studies suggest the disease burden may alter the cytokine profile of helper T cell responses to cancer antigens. We studied cytokine production by helper T cells responding to vaccination with 6 melanoma helper peptides (6MHP) in blood and lymph nodes.

Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine.

Immunization with a combination melanoma helper peptide (6MHP) vaccine has been shown to induce CD4(+) T cell responses, which are associated with patient survival. In the present study, we define the relative immunogenicity and HLA allele promiscuity of individual helper peptides and identify helper peptide-mediated augmentation of specific CD8(+) T cell responses. Thirty-seven participants with stage IIIB-IV melanoma were vaccinated with 6MHP in incomplete Freund's adjuvant.

T cells in the human metastatic melanoma microenvironment express site-specific homing receptors and retention integrins.

T-cell infiltration into the metastatic melanoma microenvironment (MME) correlates with improved patient survival. However, diffuse infiltration into tumor occurs in only 8% of melanoma metastases. Little is known about mechanisms governing T-cell infiltration into human melanoma metastases or about how those mechanisms may be altered therapeutically.

Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund's adjuvant, with or without peptide.

We conducted a randomized clinical trial in 45 patients with resected AJCC stage IIB-IV melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund's adjuvant (IFA) alone, or a melanoma vaccine in IFA. At a primary vaccine site, all patients received a multi-peptide melanoma vaccine in IFA. At a replicate vaccine site, which was biopsied, group 1 received IFA only; group 2 received vaccine in IFA.

A randomized phase II trial of multiepitope vaccination with melanoma peptides for cytotoxic T cells and helper T cells for patients with metastatic melanoma (E1602).

Purpose: This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma.

Experimental Design: One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CTL (12 MP, group A), plus a tetanus peptide (group B), or a mixture of 6 melanoma helper peptides (6 MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6 melanoma helper peptide (6 MHP) alone (group D), in incomplete Freund's adjuvant plus granulocyte macrophage colony-stimulating factor. CTL responses were assessed using an in vitro-stimulated IFN-γ ELIspot assay, and HTL responses were assessed using a proliferation assay.

Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: a phase II trial (CTEP 7190/Mel47).

Purpose: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma.

Experimental Design: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.