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Hot Research Topics

This section allows you to fully explore hot research areas such as immune checkpoint, CAR-T therapy, cancer immunotherapy, and cancer drug targets. In these pages, you can find a full list of key molecules relevant to each area, and links to our reagents for studying those molecules. As a leading reagents provider, Sino Biological is dedicated to offering high-quality recombinant proteins, antibodies, kits and other products to research labs and the drug discovery industry.

Influenza Virus Research

All Oncology Research

Immune Checkpoints

Fig. 1 Schematic diagram of immune checkpoint interaction

Immune checkpoint therapies have attracted amounts of attention from scientists who are devoted to cancer treatment. What is immune checkpoint? It is a kind of co-stimulatory and inhibitory signal for regulating the antigen recognition of T cell receptor (TCR) in the process of immune responce. When immune system is attacking pathogens, these immune checkpoint molecules can protect the normal tissues from damage. The cancer cells cleverly escape from immune attack by dysregulating immune checkpoint related proteins. Immune checkpoint therapy relys on functioning immune system with agonists of co-stimulatory signals or antagonists of inhibitory signals. Over these years there are two immune checkpoint receptors that have been actively studied: cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4 / CD152) and programmed cell death protein 1 (PD1 / PDCD1 / CD279). The corresponding antibodies can inhibit the functioning of the receptors and enhance antitumour immunity. Furthermore, multiple additional immune checkpoints, representing promising targets for anti-cancer therapy are under active development, more therapies based on immune checkpoint for more cancers are on the way to the market.

Adenosine A2a receptor

CAR-T Cell Therapy

Two landmark events occurred for CAR-T cell therapy in 2017: two anti-CD19 CAR-T cells were approved by FDA for the therapy of acute lymphoblastic leukemia (ALL) and relapsed or refractory large B-cell lymphoma, respectively. From then, increasing number of researchers have been dedicated to CAR-T cell therapy research.
What is CAR-T cell therapy？It is a kind of cell immunotherapy featured by its distinct research procedures (depicted in Fig. 1): Peripheral blood is collected from the patient firstly. Then T cells are isolated and stimulated. The cells are cultured and expanded after genetically engineered to express chimeric antigen receptors (CARs), which can recognize a specific tumor associated antigen, such as CD19, BCMA and CD20. Finally, the CAR-T cells will go through quality control and are reinfused into the patient.
Sino Biological Inc. provides not only quality CAR-T cell therapy target proteins, but also varied research reagents for the whole process of CAR-T cell therapy, such as high-quality cytokines, T cell related FACS antibodies, T cell activation antibodies, cytokine ELISA kits, apoptosis detection kits, Sinofection tranfection reagents and Supernuclease.

Fig. 1 CAR-T Cell Therapy Procedures

CAR-T Cell Therapy Targets

Sino Biological Inc. have successfully developed over 6000 proteins, covering most of the investigational CAR-T cell therapy targets. We have developed biotinylated proteins and fluorescent labeled proteins to simplify your research procedures. The proteins with high purity and binding activity, have been validated in high-class citations.

Solid tumor targets

Hematologic cancer Targets

Other CAR-T Cell Therapy Related Research Reagents

High-quality cytokines for CAR-T cell expansion and culturing

Cytokine ELISA kits to determine T cell function and cytokine storm

Cancer Immunotherapy

Cancer Immunotherapy Related Molecules (Proteins, Antibodies, ELISA Kits and Genes in Sino Biological)

Cancer Immunotherapy: Significant Information

Immunotherapy drugs for cancer

Immunotherapy Drugs for Cancer: Review

Cancer immunotherapy drugs: immune checkpoint inhibitors

Ipilimumab——The first drug to receive approval by the Food and Drug Administration (FDA) for the treatment of advanced melanoma, blocks the activity of a checkpoint protein known as CTLA4, which is expressed on the surface of activated immune cells called cytotoxic T lymphocytes.
Nivolumab——Nivolumab is approved by FDA to treat some patients with advanced melanoma or advanced lung cancer targeting a checkpoint protein on activated T cells known as PD-1.
Pembrolizumab——pembrolizumab is approved by FDA to treat some patients with advanced melanoma targeting a checkpoint protein on activated T cells known as PD-1.

Cancer immunotherapy drugs: targeted monoclonal antibodies

Rituximab——Targeting a protein on the surface of B lymphocytes called CD20,approved to be used alone or with other drugs to treat: B-cell non-Hodgkin lymphoma (certain types) and Chronic lymphocytic leukemia (CLL).
Cetuximab——In combination with radiation therapy for the initial treatment of locally or regionally advanced SCCHN; as a single agent for patients with SCCHN for whom prior platinum-based therapy has failed; and palliative treatment of pretreated metastatic EGFR-positive colorectal cancer.
Trastuzumab——ERBB2-positive breast cancer, as a single agent or in combination with chemotherapy for adjuvant or palliative treatment; ERBB2-positive gastric or gastro-oesophageal junction carcinoma as first-line treatment in combination with cisplatin and capecitabine or 5‑fluorouracil.

Cancer immunotherapy drugs: cancer vaccines

Sipuleucel-T—— In 2010, the FDA approved the first cancer treatment vaccine, sipuleucel-T (Provenge®), for use in some men with metastatic prostate cancer.
Bacillus Calmette-Guérin (BCG)——the first biological therapy to be approved by the FDA. Approximately 70 percent of patients with early-stage bladder cancer experience a remission after BCG therapy.

Cancer immunotherapy drugs: cytokines

Aldesleukin——IL-2 that is made in a laboratory, has been approved for the treatment of metastatic kidney cancer and metastatic melanoma.
Numerrous cancer immunotherapy drugs are under reseach and clinical trails now. And more and more drus will be approved used for cancer treatments.

Immunotherapy Drugs for Cancer: Reference

Scott A M et al. Antibody therapy of cancer[J]. Nature Reviews Cancer, 2012, 12(4): 278-287.
Disis ML et al. Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. Journal of Clinical Oncology 2009;27(28):4685-4692.

Side effects of immunotherapy cancer

Side Effects of Immunotherapy for Cancer: Review

The side effects of immunotherapy for cancer are as diverse as the type of treatments that have been devised. and many of the side effects are treatable.

Side effects of immunotherapy for cancer: cancer vaccines

Cancer vaccines usually have low toxicity, perhaps because they target antigens abundant on tumor cells but seldom found on normal cells.
For example, sipuleucel-T (Provenge, Dendreon Corporation), the only cancer vaccine currently approved by the FDA, generally has low toxicity. Its most common side effects include back pain and chills, seen in 2% of patients. Fewer than 4% of patients develop grade 3 or 4 adverse events.

Side effects of immunotherapy for cancer: cytokines

In 1992, the FDA approved recombinant human interferon alfa (IFN) for treating hairy cell leukemia and as an adjuvant in high-risk melanoma. The FDA approval of high-dose interleukin-2 (IL-2) in advanced renal cell carcinoma or melanoma followed in 1998. Use of either agent frequently results in severe adverse events, with vascular leak a particular problem.
More than 80% of patients who receive IFN develop fever and fatigue, the latter of which can be dose- or treatment-limiting. Patients also commonly report headache and myalgias, often controlled by nonsteroidal anti-inflammatories.
Patients may also develop severe, though uncommon, neuropsychiatric symptoms with IFN. Up to 45% develop depression, but suicide is rarely reported. For these reasons, IFN is contraindicated in patients with a history of severe depression.
Other common side effects with IFN include diarrhea, seen in about one third of patients, as well as nausea and anorexia, seen in two thirds. Both are treatable with over-the-counter medications and antiemetics. About 10% of patients develop thrombocytopenia and leukopenia, and 15% develop hyper- or hypothyroidism.
Patients who receive IL-2 often experience fever, chills, fatigue, and GI symptoms. IL-2 increases vascular permeability and can cause pleural effusions, pulmonary edema, kidney failure, and hypotension. The latter, though often dose-limiting, can be managed outside the ICU with pressor support and cardiac monitoring. Most Il-2 adverse events resolve by holding or discontinuing the medication.

Side effects of immunotherapy for cancer: adoptive cell therapy

Life-threatening autoimmunity can result when a receptor targeting self is engineered into a T-cell or when receptor-engineered T-cells cross-react with antigens in different organs.
Use of preparative chemotherapy can lead to immunosuppression and sepsis, which accounts for 1% to 2% of treatment-related mortality in these regimens.
Cytokine release syndrome (CRS) may also develop with adoptive cell therapies. Similar to sepsis, symptoms of CRS include fever, tachycardia, vascular leak, oliguria, hypotension, and organ failure, which is reversible with supportive care.
Life-threatening toxicities can be managed with high-dose corticosteroids and alemtuzumab.

Side effects of immunotherapy for cancer: immune checkpoint inhibitors

A “significant” number of patients who receive these therapies develop autoimmune syndromes. Dr Weber advises clinicians to be on the lookout for inflammation in various organs, such as colitis, pancreatitis, pneumonitis, hepatitis, hypophysitis, and skin reactions.
Immune-related adverse events follow a specific pattern, with most developing by week 24. Rashes and GI toxicities develop first, followed by liver and endocrine abnormalities. Other immune- related adverse events include arthralgias, enteritis, encephalitis, Guillain-Barre syndrome, myasthenia gravis–like syndrome, and autoimmune bone marrow suppression.
“Nearly all” of the adverse effects of these drugs resolve with treatment with high-dose corticosteroids, say the authors. Infliximab (Remicade, Janssen Biotech, Inc) may become necessary when colitis fails to resolve or relapses occur.

Side effects of immunotherapy for cancer: monoclonal antibodies

Monoclonal antibodies are given intravenously (injected into a vein). The antibodies themselves are proteins, so giving them can sometimes cause something like an allergic reaction. This is more common while the drug is first being given. Possible side effects can include:Fever, Chills, Weakness, Headache, Nausea, Vomiting, Diarrhea, Low blood pressure, Rashes.
Compared with chemotherapy drugs, naked mAbs tend to have fewer serious side effects. But they can still cause problems in some people. Some mAbs can have side effects that are related to the antigens they target. For example:
Bevacizumab (Avastin®) is an mAb that targets a protein called VEGF that affects tumor blood vessel growth. It can cause side effects such as high blood pressure, bleeding, poor wound healing, blood clots, and kidney damage.
Cetuximab (Erbitux®) is an antibody that targets a cell protein called EGFR, which is found on normal skin cells (as well as some types of cancer cells). This drug can cause serious rashes in some people.
Conjugated antibodies can be more powerful than naked mAbs, but they can also cause more side effects. The side effects depend on which type of substance they’re attached to.
Although the side effects of cancer immunotherapy are various, they are based on similar mechanisim, and can be treatable.

Side Effects of Immunotherapy for Cancer: Reference

Weber J S et al. Toxicities of Immunotherapy for the Practitioner[J]. Journal of Clinical Oncology, 2015, 33(18): 2092-2099.

Cancer immunotherapy clinical trials

Cancer Immunotherapy Clinical Trials: Review

There are several phases of clinical trials in cancer immunotherapy. Because the overwhelming majority of immunotherapies are still in the experimental phase, this focuses on phases I, II, and III trials, the trials that occur before a treatment is approved. Each phase is designed to answer certain questions. As such, there are different factors related to each trial phase to take into consideration when choosing a trial that might be right for you.

Phase I clinical trials in cancer immunotherapy

Phase I trials are conducted to determine safety and to identify the optimal treatment dose. Many phase I trials represent the first time that a particular drug is being tested in patients. Although this entails some risks, there are always guidelines built into trials to ensure patient safety, such as provisions for conservative dose escalation and to terminate trials if there is evidence of serious adverse effects. Phase I trials are small and typically enroll 15 to 30 patients.

Phase II clinical trials in cancer immunotherapy

Phase II trials are larger trials to test for signs of clinical efficacy of a treatment, usually in a more defined cohort of patients, such as patients with a specific cancer type. Phase II trials are larger than phase I trials and may enroll up to 100 patients.

Phase III clinical trials in cancer immunotherapy

Phase III trials include large numbers of patients, often hundreds to several thousands, and are designed to test if a new treatment is better than the current standard of care. Often, phase III trials are randomized, which means that some patients will receive the experimental treatment and others, in the control group, will not. Regardless, all patients will receive the standard of care, whether they are in the treatment or control group.
New drugs must go through clinical trials before they can be approved by the U.S. Food and Drug Administration (FDA) and other regulatory agencies.

Breakthrough of cancer immunotherapy

Breakthrough of Cancer Immunotherapy: Review

From 1960s, numerous progresses have been made in the area of cancer immunotherapy.
In the1960s and 70s,cancer immunotherapy was focused on intratumoral bacterial products or extracts such as Bacille Calmette-Guerin (BCG).
In the 1970s and 1980s, studies in cancer immunotherapy is about cancer vaccines with using whole autologous or allogeneic tumor cells. Lymphocyte subsets and cytokines such as interferons(IFN-α) and interleukin 2 (IL-2) that induced growth and activation of T cells and natural killer cells were discovered and introduced.
In 1990s, increased attention was given to the concept that effective immunotherapy was limited by regulatory mechanisms for controlling immune activation and an immunosuppressive tumor microenvironment. Several factors were implicated, including inhibitory ligand-receptor interactions that limited T-cell activation and function (CTLA-4), immunosuppressive cytokines (eg, transforming growth factor [TGF]-β, IL-4, IL-6, and IL-10), immunosuppressive cells (eg, T-regulatory cells [Tregs], myeloid-derived suppressor cells, and granulocytes), and cell signaling disruption (via class1 antigen loss, down-modulation of T-cell receptor [TCR] zeta chain expression, and indolamine dioxide secretion).
At the end of 20th century, Two clinical approaches, which entered the clinic within a short period of each other at the end of the century, heralded the new era of cancer immunotherapy. The first is tumor-infiltrating lymphocyte (TIL) therapy, and the second is substantial anti-tumor effects of blocking specific factors, most prominent the inhibitory ligand–receptor interactions, that served as physiologic brakes on the immune system.The CTLA-4 monoclonal antibody, receivec the US Food and Drug Administration (FDA) approval in 2011 for the treatment of patients with advanced melanoma. The broad clinical activity of anti–PD-1 and anti–PD-L1 energized thepharmaceutical and biotechindustry to initiate or expand preclinical and clinical research programs for cancer immunotherapy agents.
Now, combination immunotherapy is on the way to success.

Breakthrough of Cancer Immunotherapy: Reference

Atkins M B et al. Cancer Immunotherapy: Past Progress and Future Directions[C]//Seminars in oncology. Elsevier, 2015, 42(4): 518-522.
Morton DL et al.BCG immunotherapy of malignan tmelanoma:summary of a seven-year experience. AnnSurg.1974;180(4):635–43.

Companies of cancer immunotherapy

Cancer Immunotherapy Companies: Review

As cancer immunothrerapy has become more and more popular in research, a lot of companies have focused on this area to seek for ways for cancer treatments. 10 most famous cancer immunotherapy companies are listed here:

Incyte Corporation

Incyte put their efforts on immune checkpoint inhibitors. The most famous are IDO inhibitors, PD-1 inhibitors under clinical trials.

Juno Therapeutics

The use of human T cells as therapeutics to re-engage the immune system has the potential to revolutionize the way cancer is treated. Juno’s technologies genetically engineer a patient’s own T cells to recognize and kill cancer cells. These cellular therapies have the potential to be effective regardless of the type of previous treatments patients have experienced and may avoid the long-term side effects associated with current treatments. Two different technologies are used to target cancer cells and activate T cells, CARs and TCRs.

Bluebird bio

Cancer immunotherapy research group in bluebird is based on CAR T cells presents a promising new treatment option. They focused on the next generation of T cell engineering and creating a pipeline of T cell product candidates to treat a wide variety of liquid and solid tumor cancers. based on CAR T cells presents a promising new treatment option.

Celldex Therapeutics

Celldex’s pipeline is comprised of therapeutic antibodies, antibody drug conjugates, immune system modulators and vaccines.

Tesaro, Inc.

In Tesaro, Inc., by blocking the interaction of PD-1, TIM-3 and LAG-3 with their respective ligands, antibodies to these targets aim to restore immune anti-cancer function in patients across a variety of tumor types.

Kite Pharma

They are developing engineered autologous T cells that express either a chimeric antigen receptor (CAR) or a T cell receptor (TCR), depending on the type of cancer. Their dual platform has the potential to address both hematological and solid tumor cancers.

NewLink Genetics

Their immuno-oncology pipeline includes HyperAcute® Cellular Immunotherapies and small molecule product candidates, such as cellular immunotherapy IDO inhibitor, and designed to harness multiple components of the immune system to combat a wide range of cancers without significant incremental toxicity, either as monotherapy or in combination with other treatment regimens.

ZIOPHARM Oncology

ZIOPHARM Oncology and its partner Intrexon Corporation, a leader in synthetic biology, together with collaborators at The University of Texas MD Anderson Cancer Center, are employing novel cell engineering techniques and multigenic gene programs to develop next-generation patient- and donor-derived adoptive cellular therapies based on designer cytokines, such as genetically modified T cells and NK cells, to target hematologic malignancies and solid tumors as well as graft-versus-host-disease. These technologies are designed to improve safety and decrease the cost, time and complexity of development associated with cell-based therapies.

Atara Biotherapeutics

T-cell product candidates include Epstein-Barr virus (EBV)-targeted cytotoxic T lymphocytes (CTLs), cytomegalovirus (CMV)-targeted CTLs, and Wilms Tumor 1 (WT1)-targeted CTLs. These T-cell product candidates are designed to target cancer cells or cells infected with certain viruses and kill them. Each product candidate is designed to address the underlying mechanisms of disease to treat conditions which have few therapeutic options today.

Cellectis

Cellectis is a pioneering gene editing company, employing core proprietary technologies to develop best-in-class products in the emerging field of immuno-oncology. Our product candidates, based on gene-edited T-cells that express Chimeric Antigen Receptors, or CARs, seek to harness the power of the immune system to target and eradicate cancers.
More and more companies have participated in the range of cancer immuotherapy research, which will offer new hope for cancer therapeutic research.

Cancer Immunotherapy Treatment

Cancer immunotherapy: monoclonal antibodies

Monoclonal Antibody for Cancer Immunotherapy: Review

Monoclonal antibody for cancer immunotherapy has become established over the past 15 years and is now one of the most successful and important strategies for treating patients with haematological malignancies and solid tumours.
Monoclonal antibody functions in cancer immunotherapy more than three ways, targeting cancer associated antigen and immune modulating molecules:
(1) Monoclonal antibody kill tumor directly (through receptor blockade or agonist activity, induction of apoptosis, or delivery of a drug or cytotoxic agent). Cetuximab, for instance, a chimeric EGFR-specific IgG1 monoclonal antibody, functions by preventing binding of activating ligand and by preventing receptor dimerization, a crucial step for initiating EGFR-mediated signal transduction.
(2) Immune-modulated cell killing mechanisms (including, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and regulation of T cell function). Many tumours have been shown to express CD40, including carcinomas of the ovary, nasopharynx, bladder, cervix, breast and prostate, and the engagement of CD40 can lead to a direct antitumour effect in some tumours in vivo. In one study, the effect of a fully human CD40-specific agonist monoclonal IgG2 was assessed in 29 patients with advanced solid tumours. The results showed four partial responses (all patients with melanoma) and one complete resolution.
(3) Specific effects of monoclonal antibody on tumour vasculature and stroma. Bevacizumab, a VEGFA-specific humanized monoclonal antibody, blocks binding of VEGF to its receptor and is approved for the treatment of breast, colorectal and non-small-cell lung cancer in combination with cytotoxic chemotherapy.
Since 1997, more than 10 antibodies have received approval from the FDA for the cancer immunotherapy of various solid tumours and haematological malignancies, such as monoclonal antibodies for ERBB2, VEGF, EGFR, CTLA4, CD20, CD52, CD33, and CD30, and a large number of additional therapeutic antibodies are currently being tested in early stage and late-stage clinical trials. With the development of combining monoclonal antibody for cancer immunotherapy with other therapy method, More and more afficacies will be achieved.

Monoclonal Antibody for Cancer Immunotherapy: Reference

Weiner L M, et al. Monoclonal antibodies: versatile platforms for cancer immunotherapy[J]. Nature Reviews Immunology, 2010, 10(5): 317-327.
Scott A M, et al. Antibody therapy of cancer[J]. Nature Reviews Cancer, 2012, 12(4): 278-287.

Adoptive immunotherapy for cancer

Adoptive Immunotherapy for Cancer: Review

Adoptive immunotherapy, or the infusion of lymphocytes, is a promising approach for the treatment of cancer. What is adoptive immunotherapy for cancer? Adoptive immunotherapy for cancer is a treatment used to help the immune system fight cancer. T cells are collected from a patient and grown in the laboratory. This increases the number of T cells that are able to kill cancer cells. These T cells are given back to the patient to help the immune system to fight disease. Also called cellular adoptive immunotherapy.
The early promise of adoptive immunotherapy is now coming to fruition with exciting clinical responses being reported against various cancers. This has particularly been the case with adoptive transfer of tumor-infiltrating lymphocytes in patients with advanced malignant melanoma, transfer of chimeric antigen receptor (CAR) T cells targeting CD19 in patients with B-cell malignancies such as chronic lymphoid leukemia and acute lymphoblastic leukemia and transfer of Epstein–Barr virus (EBV)-specific T cells against viral-induced malignancies such as post-transplant lymphoproliferative disorder(PTLD).

Adoptive Immunotherapy for Cancer： Tumor-infiltrating lymphocytes (TILs)

Adoptive T cell immunotherapy based on tumor infiltrating lymphocytes is the most effective treatment for cancer of malignant melanoma. The tumor infiltrating lymphocytes immunotherapy has demonstrated high overall response rates, resulting in cancer regression and prolonged survival in comparison to IL-2 and ipilimumab treatments.

Adoptive Immunotherapy for Cancer： Chimeric antigen receptor (CAR) T-cell

The technique of chimeric antigen receptor (CAR) T-cell for cancer immunotherapy has shown very encouraging results in early clinical trials against some advanced, hard-to-treat types of leukemias and lymphomas.

Adoptive Immunotherapy for Cancer： Epstein–Barr virus (EBV)-specific T cells

Epstein–Barr virus (EBV)-specific T cells immunotherapy have been most successful as prophylaxis and therapy for post-transplant lymphoproliferative disease (PTLD), which expresses the full array of latent EBV antigens (type 3 latency), in hematopoietic stem cell transplant recipients.
Although much progresses have been made, for application of adoptive immunotherapy for cancer to a wider range of solid and hematological cancers, several challenges remain with nemerous corresponding strategies and developments. It is anticipated that these developments will have a significant impact on the treatment of cancer patients with advanced metastatic disease in the future

Adoptive Immunotherapy for Cancer: Reference

Darcy P K et al. Adoptive immunotherapy: a new era for the treatment of cancer[J]. Immunotherapy, 2015, 7(5): 469-471.
Maus M V et al. Adoptive immunotherapy for cancer or viruses[J]. Annual review of immunology, 2014, 32: 189.

Cancer immunotherapy: vaccines

Vaccines for Cancer Immunotherapy: Review

In theory at least, for immunotherapy, a therapeutic cancer vaccine has the potential to stimulate specific immunity against tumors while sparing normal tissues, leading not only to tumor lysis but also to the induction of a long lasting, systemic immunological memory that protects against recurrent disease and metastasis. Three major vaccine strategies emerged:

Peptide/Protein vaccines in cancer immunotherapy

(1) Defined tumor antigen vaccines are based on specific gene products, and can come in the form of peptides, full-length proteins, or genetically encoded vectors. NY-ESO-1, MAGE-A3, gp100, MART-1, Muc1 and some other antigens have been developped as vaccines. The data in the past research highlight several major challenges for cancer vaccines based on peptides and proteins regardless of design and tumor type: (a) antigen/epitope selection for optimal binding to MHC molecules; (b) suitable adjuvant for each vaccine based on antigen property and desired immunological outcome; (c) presence of regulatory cells that suppress immune activation; and (d) effector cell exhaustion.

Whole tumor cell vaccines in cancer immunotherapy

(2) Whole-cell cancer vaccines employ the entire tumor cell and, in the cases of autologous tumors, the associated tumor stroma and vasculature, to potentiate immune activation. For whole cell cancer vaccines, retroviral or adenoviral transduction of tumor cells to express molecules relevant for immune activation has been explored as another strategy to improve tumor immunogenicity. Of many immunostimulatory mediators evaluated in the context of gene-modified tumor cell vaccines, GM-CSF emerged as the most potent in generating protective antitumor immunity.

Ex vivo dendritic cell vaccines in cancer immunotherapy

(3) A third approach involves the direct loading of whole tumor material or defined antigen to autologous DCs ex vivo followed by inoculation into patients. Mature DCs mediate three critical functions central for the clinical success of a cancer vaccine: (a) the capture of extracellular tumor-derived peptides or full-length proteins and subsequent processing to produce MHC-peptide complexes; (b) migration into lymph node for presentation of peptide–MHC complexes to T cells; (c) expression of costimulatory molecules, such as CD80, CD86, and CD40L, and production of cytokines such as IL-12 that are required for effector T cell activation and differentiation. In patients with late stage disease, who are typically enrolled in various vaccine studies, systemic immunosuppression is common and could further hinder immune activation. Based on these observations, a therapeutic vaccination strategy in which autologous DCs are expanded and activated with cytokine combinations and then loaded with antigens was developed. Sipuleucel T, an autologous vaccine consisting of peripheral blood mononuclear cells pulsed with a fusion protein composed of full-length prostatic acid phosphatase and GM-CSF (to enhance antigen-presenting cell function) was approved by the FDA in 2010 as the first cell-based cancer immunotherapy, based on an overall survival benefit of 4 months in metastatic prostate cancer patients.
Many approaches to therapeutic cancer vaccines have been explored, with varying levels of success. However, with the exception of Sipuleucel T, no therapeutic cancer vaccine has yet shown clinical efficacy in phase 3 randomized trials. Though disappointing, lessons learned from these studies have suggested new strategies to improve cancer vaccines.

Vaccines for Cancer Immunotherapy: Reference

Wong K K, et al. Advances in Therapeutic Cancer Vaccines[J]. Advances in Immunology, 2016.
Kaufman, H. L et al. Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): A trial of the Eastern Cooperative Oncology Group. Journal of Clinical Oncology, 22, 2122.

Tumor-infiltrating lymphocytes (TILs) for cancer immunotherapy

Tumor-infiltrating lymphocytes (TILs) for cancer immunotherapy: Review

Adoptive T cell immunotherapy based on tumor infiltrating lymphocytes is the most effective treatment for cancer of malignant melanoma. Tumor-infiltrating lymphocytes (TILs) for cancer immunotherapy is about that T cells can be removed from tumor samples taken from patients and multiplied in the lab by treating them with IL-2. Then the T cells are injected back into the patient for a treatment. The tumor infiltrating lymphocytes immunotherapy has demonstrated high overall response rates, resulting in cancer regression and prolonged survival in comparison to IL-2 and ipilimumab treatments.

Tumor-infiltrating lymphocytes (TILs) for cancer immunotherapy of melanoma

The first clinical pilot study using Tumor-infiltrating lymphocytes was reported in 1988 for metastatic melanoma. The study was performed on 12 patients who were treated with variable doses and combination of Tumor-infiltrating lymphocytes, IL-2 and cyclophosphamide. The result demonstrated partial response in 2 patients and partial regression in 1 patient. Tumor specific cytolytic activity was observed in 5 patients. The study demonstrated the possibility of treating the patients with a combined approach. In another report published in same year, 20 melanoma patients were treated with Tumor-infiltrating lymphocytes and IL-2 preconditioned with a single dose of cyclophosphamide. Objective response was observed in 9 patients who did not receive IL-2 and 2 patients in whom previous IL-2 therapy failed. These initial reports indicated that Tumor-infiltrating lymphocytes treatment regimen may provide higher response rate in melanoma patients. In continuation of the above studies Rosenberg et al (1994) treated 86 patients of metastatic melanoma with autologus Tumor-infiltrating lymphocytes and high dose of IL-2. Overall objective response rate of 35% was observed in patients who received cyclophosphamide and 31% in those who did not. In another study by Rosenberg et al (2011) three sequential clinical trials were performed in which 93 patients (metastatic melanoma) were treated with lympho depleting preparative regimen (chemotherapy alone or chemo with 2Gy or 12Gy irradiation), autologous Tumor-infiltrating lymphocytes and IL2. Objective response rates by RECIST criteria in the three trials were 49%, 52% and 72%, respectively. Study showed that 22% of all patients achieved complete tumor regression and 19% of the patients were disease-free for more than three years.

Tumor-infiltrating lymphocytes (TILs) for cancer immunotherapy of colorectal cancers

Galon et al (2006) studied Tumor-infiltrating lymphocytes in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. The data analysis suggested that immunological parameters were better predictors of patient survival than the histopathological methods. Furthermore, in situ data analysis suggested that Tumor-infiltrating lymphocytes might act as a valuable prognostic tool in the treatment of colorectal cancer. Pages et al (2009) evaluated the treatments of cytotoxic (CD8) and memory (CD45RO) T cells in patients with early-stage colorectal cancer. The results gave valuable information regarding tumor recurrence and survival in patients with early-stage colorectal cancer.

Tumor-infiltrating lymphocytes (TILs) for cancer immunotherapy of breast cancer

Gingras et al (2015) critically reviewed the relationship between immunity and breast carcinoma. Mahmoud et al (2011) studied clinical outcome of the Tumor-infiltrating lymphocytes treatment in breast cancer patients. The results suggested that tumor-infiltrating CD8+ T lymphocytes had antitumor activity and could potentially be exploited in the treatment of breast cancer. Since there has been an increase in the use of molecular fingerprint analysis in the field of cancer research, standard prognostic, predictive and diagnostic parameters are ever changing. Continued research in Tumor-infiltrating lymphocytes can further our understanding in tumor immunotherapy and improve effectiveness of therapies.
Tumor-infiltrating lymphocytes have shown good effectiveness in treating melanoma and other multiple groups of malignancies such as breast and brain metastasis. Tumor-infiltrating lymphocytes for cancer immunotherapy. There have also been some clinical trials that failed to produce good results with Tumor-infiltrating lymphocytes. needs further in-depth investigations on combination approaches that can improve long term efficacies and reduce the cost to a more affordable level.

Tumor-infiltrating lymphocytes (TILs) for cancer immunotherapy: Reference

Bora C R et al. Trends in Adoptive Tumor Infiltrating Lymphocytes (TILs) Therapy[J]. BAOJ Cancer Res Ther, 2015, 2(006).
Qian X, W et al. Cell Transfer Therapy for Cancer: 2. Past, Present, and Future. J of Immuno Research vol. 2014, Article ID 525913, 9 pages.

Cancer Drug Targets

Targeted therapy is an effective method for cancer, which shows instinct advantages over chemical therapy. The appropriate selection of drug targets is the key to the the success in cancer therapy. A common part of the targets are influencing cell growth and survival, and proliferation, and related to cell signalling pathways, such as EGFR, HER2, ALK, mTOR, RAF. Some of the drug targets are closely involved in pathological angiogenesis, such as VEGF/VEGFR, PDGFR, MEK. Recently, immune checkpoints have been hot targets in cancer therapy, especially, PD-1, PD-L1 and CTLA4, the monoclonal antibody drugs of these targets have performed great efficacies and deep potentials in the therapy of multiple cancers.

Drug Targets for Cancer: Bioreagents

We provide proteins, antibodies, genes and ELISA kits of numerous drug targets to support your cancer research.

Targeted Therapy

What is Targeted Therapy in Cancer

For cancer treatment, the initial method of chemotherapeutic agents has been cytotoxic drugs. Their action of mitotic inhibition is not limited to cancer cells, particularly profound effects being seen on the haematopoietic system, often with resulting neutropenia or pancytopenia. Targeted therapy conversely seeks to selectively affect cancer cells based on specific molecular characteristics. Targets for therapy are diverse but involve cellular growth, proliferation and, more recently, immune evasion. What is targeted therapy? Targeted therapy is a newer type of cancer treatment that uses drugs or other substances to more precisely identify and attack cancer cells, usually while doing little damage to normal cells.It has been validated to be a curative treatment for cancer, with many clinical trials and approved by FDA.

Types of Targeted Therapy

Tyrosine kinase inhibitors, such as erlotinib, gefitinib and afatinib, are orally active small molecules that act intracellularly to prevent downstream signal transduction from activated growth factor receptors. They have demonstrable efficacy in non-small cell lung cancers (NSCLCs) harbouring activating EGFR mutations.

Monoclonal antibodies utilize the specificity of the fragment antigen-binding region of the antibody to target specific therapeutic epitopes. Modern antibodies are either chimeric mouse ehuman or fully human, with the latter felt to be less immunogenic. They target either extracellular ligands (the compounds that activate the receptor), for example bevacizumab on vascular endothelial growth factor (VEGF), or the cell surface receptors themselves, for instance cetuximab on EGFR. Bevacizumab and cetuximab have demonstrated efficacy in colorectal cancers. Similarly to chemotherapy, they are usually delivered by intravenous infusion.

Antibody drug conjugates combine a monoclonal antibody with a cytotoxic to deliver the cytotoxic directly to the targeted cells. The antibody targets and binds to a specific extracellular receptor, leading to internalization of the complex, thus delivering the cytotoxic payload only to those cells expressing the targeted receptor. TDM-1 is a conjugate of trastuzumab and the cytotoxic emtansine and has been shown to improve survival in patients with metastatic human epidermal growth factor 2 receptor (HER2) positive breast cancer.

Immune checkpoint inhibitors are monoclonal antibodies that target key regulatory points in the cellular immune system such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). As with growth factor-targeting antibodies, they target either the receptor (e.g. the anti-CTLA-4 monoclonal antibody ipilimumab or the anti-PD-1 antibody nivolumab) or the ligand (e.g. programmed cell death ligand 1 (PD-L1). They facilitate immune recognition and destruction of cancer cells, and have proven efficacy in malignant melanoma and NSCLC.

Hormonal agents used for breast and prostate cancer comprise a variety of agents that target ligand synthesis or binding with intracellular hormonal receptors. Agents include peptides (gonadotropin-releasing hormone (GnRH)antagonists and agonists), steroidal antiandrogens (e.g. abiraterone acetate) and non-steroidal antiandrogens (e.g. enzalutamide).

How does Targeted Therapy Work

Targeted cancer therapies are drugs designed to interfere with specific molecules necessary for tumor growth and progression. Traditional cytotoxic chemotherapies usually kill rapidly dividing cells in the body by interfering with cell division. A primary goal of targeted therapies is to fight cancer cells with more precision and potentially fewer side effects.

Therapeutic monoclonal antibodies target specific antigens found on the cell surface, such as transmembrane receptors or extracellular growth factors. In some cases, monoclonal antibodies are conjugated to radio-isotopes or toxins to allow specific delivery of these cytotoxic agents to the intended cancer cell target. Some examples are bevacizumab, humanized monoclonal antibody targeting VEGF-A; cetuximab, chimeric monoclonal antibody targeting EGFR; and ipilimumab, fully human antibody with an immune system target CTLA-4.

Small molecules can penetrate the cell membrane to interact with targets inside a cell. Small molecules are usually designed to interfere with the enzymatic activity of the target protein. Some examples are bortezomib, a small molecule proteasome inhibitor; imatinib, a small molecule tyrosine kinase inhibitor, and seliciclib, small molecule cyclin-dependent kinase inhibitor.

The FDA has approved multiple targeted drug cancer therapies, and many more are being studied in clinical trials either alone or in combination with other treatments.

Targets of Targeted Therapy Research

Cancer Biomarkers

Cancer Biomarker Background

Cancer Biomarker Information

Cancer biomarkers can be used for prognosis: to predict the natural course of a tumor, indicating whether the outcome for the patient is likely to be good or poor (prognosis). They can also help doctors to decide which patients are likely to respond to a given drug (prediction) and at what dose it might be most effective (pharmacodynamics). Cancer biomarkers are present in tumor tissues or serum and encompass a wide variety of molecules, including DNA, mRNA, transcription factors, cell surface receptors, and secreted proteins. One of these serum biomarkers in wide use is PSA which is produced by normal prostate cells. The higher the PSA is in the serum, the higher the correlation is toward the existence of prostate cancer.

Prognostic biomarkers allow the natural course of a tumor to be predicted, distinguishing ‘good outcome’ tumors from ‘poor outcome’ tumors, and they guide the decision of whom to treat (or how aggressively to treat). Predictive biomarkers are used to assess the probability that a patient will benefit from a particular treatment. For example, patients with breast cancer in which the gene encoding the oestrogen receptor is expressed respond to treatment with tamoxifen, whereas when the gene ERBB2 (also known as HER2) is amplified in the tumour, the patients benefit from treatment with trastuzumab (Herceptin) instead. Pharmacodynamic biomarkers measure the near-term treatment effects of a drug on the tumor (or on the host) and can, in theory, be used to guide dose selection in the early stages of clinical development of a new anticancer drug.

The application of cancer biomarkers is still controversial. PSA is a widely used cancer biomarker. However, there are reasons other than cancer that can cause rises in PSA, such as infections within the prostate gland, increased exercise with irritation of the affected area, and even vigorous physical examination by a doctor. Cancer antigen 125 (CA-125) can be a biomarker of ovarian cancer risk or an indicator of malignancy, but it has low sensitivity and specificity. Levels of this marker can be high in people who have pancreatitis, kidney or liver disease, making its accuracy as a cancer diagnostic tool very limited. Carcinoembryonic antigen (CEA) is another biomarker that is elevated in patients with colorectal, breast, lung, or pancreatic cancer. As a screening test, it can be elevated by many other factors than cancer; smoking for instance raises CEA levels.

An ideal tumor marker should be measured easily, reliably and cost-effectively using an assay with high analytical sensitivity and specificity. In addition, an ideal tumor marker should be present in detectable quantities at early or preclinical stages and the quantitative levels of the tumor marker should reflect tumor burden. Recent technological advances, especially in the fields of genomics and proteomics, have made it easier to identify many biomarkers at once in high-throughput screens. The validation of cancer biomarkers – that is, determination of clinical relevance and applicability – is also quite challenging, and many questions have been raised regarding how new tests will be developed, evaluated, and integrated into clinical practice.

Cancer Biomarker References

1. Kulasingam V, et al. (2007) Tissue culture-based breast cancer biomarker discovery platform. Int J Cancer. 123(9):2007-12.
2. Sawyers CL. (2008) The cancer biomarker problem. Nature. 452(7187):548-52.
3. Johansen JS, et al. (2009) Plasma YKL-40: a potential new cancer biomarker? Future Oncol. 5(7):1065-82.
4. Wang P, et al. (2009) The evolving role of mass spectrometry in cancer biomarker discovery. Cancer Biol Ther. 8(12):1083-94.
5. Boffetta P. (2010) Exploring a cancer biomarker: the example of C-reactive protein. J Natl Cancer Inst. 102(3):142-3.

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