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Most cancer patients are treated with some combination of surgery, radiation, and chemotherapy. Radiation and chemotherapy have the disadvantage of destroying healthy as well as malignant cells and thus can cause severe side-effects. What is needed are more precisely-targeted therapies. One long-held dream is that the specificity of immune mechanisms could be harnessed against tumor cells. This might use the patient's own immune system or the transfer of antibodies or T cells from an outside source (i.e. passive immunization). Ideally, these agents would be targeted to molecules expressed on the cancer cells but not on healthy cells. However, such tumor-specific antigens have been hard to find, and so many of the immune agents now in use do target healthy cells as well.
There is considerable evidence that cancer patients have T cells that are capable of attacking their tumor cells. In fact, it may be that the appearance of cancer is a failure of immune surveillance: the ability of one's own immune system to destroy cancer cells as soon as they appear. But what to do if they fail? Immunostimulants are nonspecific agents that tune-up the body's immune defenses. There have been some successes with
- injecting adjuvant-like agents directly into the tumor. The only one that succeeds often enough to remain in use is the bacterial preparation BCG. Introduced into the bladder, it can help eradicate early-stage bladder tumors.
- Oral therapy with levamisole, a drug widely-used for deworming (people as well as animals), has been used to treat a variety of cancers but with inconsistent results.
- interleukin-2 (IL-2), a potent growth factor for T cells;
- alpha-interferon (IFN-α)
Cancer Therapy with Monoclonal Antibodies
A number of monoclonal antibodies show promise against cancer, especially cancers of white blood cells (leukemias, lymphomas, and multiple myeloma). Some examples:
- Rituximab (trade name = Rituxan®). Used to treat B-cell lymphomas. The CD20 molecule to which it binds is present on most B-cells, healthy as well as malignant, but over the months following treatment, new healthy B cells are formed from precursors that do not have CD20 and thus were not destroyed by the treatment.
- Trastuzumab (trade name = Herceptin®). Binds HER2, a growth factor receptor found on some tumor cells (some breast cancers, lymphomas). The only monoclonal so far that seems to be effective against solid tumors.
- Alemtuzumab (MabCampath®). Binds to CD52, a molecule found on white blood cells. Has produced remission of chronic lymphocytic leukemia.
- Lym-1 (Oncolym®). Binds to the HLA-DR-encoded histocompatibility antigen that can be expressed at high levels on lymphoma cells.
- Bevacizumab (Avastin®). Binds to vascular endothelial growth factor (VEGF) thus blocking its action and depriving the tumor of its blood supply.
- Cetuximab (Erbitux®). Used to treat colorectal cancers.
- A monoclonal antibody against CD47. CD47 is a cell-surface protein expressed at high levels in many different human cancers. CD47 blocks any effort that macrophages and dendritic cells might make to phagocytose the cancer cells; that is, CD47 is a "don't eat me" signal. A variety of human cancers transplanted into immunodeficient mice have their growth suppressed and metastases prevented when the mice are given a monoclonal antibody against CD47 thus unleashing the ability of phagocytes to destroy the cancer cells. The success in mice will soon lead to clinical trials in humans.
- Ipilimumab (Yervoy®). Unlike the other monoclonals listed here, ipilimumab acts as an immunostimulant. It does so by binding to the CTLA-4 molecules on the T cell so that they cannot bind to the B7 molecules on the antigen-presenting cell. This frees the T cell's CD28 molecules to bind B7 thus receiving the stimulatory "signal 2" from the antigen-presenting cell. Ipilimumab was approved by the U.S. Food and Drug Administration on 25 March 2011 for use against metastatic melanoma. Because its double-negative effect works to enhance the body's overall T-cell responses, it may well turn out to be useful against other cancers as well (and explains some of the autoimmune-like side effects it produces). It also provides perhaps the best evidence yet for the existence of immune surveillance; that is, the presence in the patient's body of an innate population of T cells specific for the tumor.
- Pembrolizumab and nivolumab
- Blinatumomab is a synthetic monoclonal antibody each arm of which carries a binding site with a different specificity:
- one arm binds to CD19, an antigen found on the surface of B cells and B-cell lymphomas
- the other arm binds to CD3, a cell-surface molecule on T cells, including cytotoxic T lymphocytes (CTLs)
By forming a bridge between CD3 and CD19, blinatumomab is able to attach T cells to B cells and activate the T cells to kill the B cells. Early clinical trials with blinatumomab on a small number of patients appear quite promising. Modest doses of the drug produced partial and, in a few cases, complete regression of their lymphoma.
A major problem with chemotherapy is the damage the drugs cause to all tissues where rapid cell division is going on. What is needed is a "magic bullet", a method of delivering a cytotoxic drug directly and specifically to tumor cells, sparing healthy cells. Such a magic bullet would have two parts - a monoclonal antibody specific for the cancer cell attached to a cytotoxic drug or toxin that kills the cell once it gets inside.
Some two dozen immunotoxins are in clinical trials. Two that have already received FDA approval:
- Adcetris®. The vedotin is attached to the monoclonal antibody by a bridge that is cleaved once the conjugate is safely inside the tumor cell releasing the toxin to do its work there. In one trial, 73% of the patients with Hodgkin's lymphoma went into remission.
- a monoclonal antibody that binds CD30, a cell-surface molecule expressed by the cells of some lymphomas but not found on the normal stem cells needed to repopulate the bone marrow.
- vedotin, a drug that blocks mitosis by preventing the polymerization of tubulin (needed to form the mitotic spindle).
- Kadcyla® The DM1 is attached to the monoclonal antibody by a bridge that is cleaved once the conjugate is safely inside the tumor cell releasing the toxin to do its work there. Kadcyla® prolongs survival in women whose breast cancer over-expresses HER2 (about 20% of breast cancer cases).
- Trastuzumab (Herceptin®), the monoclonal antibody against HER2 listed above;
- DM1, another drug that inhibits mitosis by preventing the polymerization of tubulin (needed to form the mitotic spindle).
Monoclonal antibodies against tumor antigens can also be coupled to radioactive atoms. The goal with these agents is to limit the destructive power of radiation to those cells (cancerous) that have been "fingered" by the attached monoclonal antibody. Examples:
- Zevalin®. This is a monoclonal antibody against the CD20 molecule on B cells (and lymphomas) conjugated to either
- the radioactive isotope indium-111 (111In) or
- the radioactive isotope yttrium-90 (90Y)
- Bexxar® (tositumomab). This is a conjugate of a monoclonal antibody against CD20 and the radioactive isotope iodine-131 (131I). It, too, is designed as a treatment for lymphoma. Although both Bexxar® and Zevalin® kill normal B cells, they don't harm the B-cell precursors because these do not express CD20. So, in time, the precursors can repopulate the body with healthy B cells.
On 3 February 2005, the New England Journal of Medicine reported that 59% of patients with a B-cell lymphoma were disease-free 5 years after a single treatment with 131I-tositumomab (a treatment that was relatively free of the nasty side-effects, e.g., hair loss, of conventional chemotherapy).
Adoptive Cell Therapy (ACT)
Tumor destruction is done by cells. Antibodies may help, but only by identifying the cells to be destroyed, e.g., by macrophages. But T cells, e.g., cytotoxic T lymphocytes (CTL), are designed to destroy target cells. What about enlisting them in the fight?
Tumor-Infiltrating Lymphocytes (TIL)
Solid tumors contain lymphocytes that are specific for antigens expressed by the tumor. For many years, Steven A. Rosenberg and his associates at the U. S. National Cancer Institute have tried to enlist these cells in cancer therapy.
On September 19, 2002, he reported his most promising results at that time. The procedure:
- Isolate T cells — both CD4+ T-helper cells and CD8+ cytotoxic T lymphocytes (CTL) from samples of the tumor (melanoma)
- Test them in vitro to find the most efficient killers of the melanoma cells.
- Grow large numbers of them in culture (using the powerful T-cell growth factor IL-2).
- Treat the patient with modest doses of cytotoxic drugs to reduce — but not destroy — the bone marrow (called nonmyeloablative conditioning).
- Reintroduce the mix of Th cells (CD4+) and CTL (CD8+) into the patient (along with IL-2).
- The infused cells usually took up long-term residence.
- In 10 of 13 patients, their melanoma cells — including all metastases — regressed either partially or completely.
In a few cases, the TIL seemed to be reacting to tumor-specific antigens, but in most the target seems to have been antigens expressed by all melanin-containing cells. Evidence:
- Four patients lost normal melanocytes from their skin leaving white patches.
- One patient developed inflammation of the uvea, the coat of melanin-containing cells within the eye.
Adoptive transfer of a clone of the patient's own tumor-antigen-specific T cells
The 19 June 2008 issue of the New England Journal of Medicine (Naomi Hunder et al) carried a report describing the successful treatment of a man with metastasized melanoma using his own T cells. The procedure:
- His leukocytes were harvested and a mixed culture was prepared containing
- antigen-presenting dendritic cells.
- a peptide from the antigen NY-ESO-1. NY-ESO-1 is a protein that is produced by several types of tumors (e.g., melanoma, lung and breast cancers) but is not expressed by normal cells (except those in the testis).
- The patient's own T cells.
- After repeated stimulation with the antigen, responding cells were cloned by limiting dilution.
- One (of four) antigen-reactive cells was then expanded in culture until
- 5 billion (5 x 109) identical anti-NY-ESO-1 CD4+ T cells were available to infuse into the patient.
The result: complete regression of each metastatic clump of melanoma cells, and the patient has remained free of this lethal cancer for two years since this treatment.
Adoptive transfer of genetically-modified T cells
Genetically engineered with a T-cell Receptor
On April 20, 2006, the Rosenberg group reported some success with melanoma patients using a modification of the TIL procedure.
- The patient's T cells were removed and treated with a retroviral vector containing the αβ T-cell receptor (TCR) specific for a melanoma antigen.
- Large numbers of these were grown in culture.
- After nonmyeloablative conditioning to "make room" for them, the genetically-modified lymphocytes were infused into the patient.
- This application of gene therapy succeeded in eliminating the metastases and providing a disease-free period of two years in two patients.
Genetically engineered with a Chimeric Antigen Receptor (CAR)
The 10 August 2011 online version of the New England Journal of Medicine carried a report by Porter, D., et al. on their results with one (of three) patients treated for chronic lymphocytic leukemia (CLL) with an infusion of his own genetically-modified T cells.
The patient's malignant B cells expressed the surface antigen CD19 just as normal B cells do.
T cells were harvested from his blood and later treated with a vector encoding the antigen-binding site of an anti-CD19 antibody along with two other costimulatory molecules. The result: some 5% of these T cells expressed this synthetic antibody (called a chimeric antigen receptor or CAR) and were activated when they bound CD19 with it (rather than with their T cell receptor (TCR) which they would normally use).
Injected back into the patient, they proliferated by some 1000-fold and persisted for months. During this period, they eliminated all his malignant B cells (as well as his normal B cells). At the time of the report (10 months after treatment), he continued to be free of his cancer. Lacking normal B cells as well, he needed periodic infusions of immune globulin to keep infections at bay.
"One swallow does not make a summer", but these results give hope that in time immunotherapy will become an effective weapon against cancer.
Any response of the patient's own immune system – immune surveillance – has clearly failed in cancer patients. The purpose of cancer vaccines is to elicit a more powerful active immunity in the patient. Several approaches are being explored.
Patient-Specific Cancer Vaccines
Patient-Specific Dendritic-Cell Vaccines
Dendritic cells are the most potent antigen-presenting cells. They engulf antigen, process it into peptides, and "present" these to T cells.
To make a dendritic-cell vaccine,
- Harvest dendritic cells from the patient.
- Expose these in vitro to antigens associated with the type of tumor in the patient.
- The antigens are found in normal – as well as cancerous – cells of that tissue (e.g., tyrosinase in melanocytes, prostatic acid phosphatase [PAP] in prostate cells).
- They may be fused with a stimulatory molecule such as granulocyte-macrophage colony-stimulating factor (GM-CSF)
- Inject these "pulsed" dendritic cells back into the patient.
- Hope that they elicit an strong cell-mediated immune response, e.g. by cytotoxic T lymphocytes (CTL).
On 29 April 2010 the U.S. Food and Drug Administration approved the first anti-cancer vaccine: a patient-specific dendritic-cell vaccine for use against advanced prostate cancer. The vaccine, called sipuleucel-T (Provenge®), is produced by pulsing the patient's dendritic cells with a fusion protein coupling prostatic acid phosphatase [PAP] with GM-CSF.
Patient-Specific Tumor-Antigen Vaccines
The antigens in these vaccines are taken from the patient's own tumor cells.
- Harvest some tumor cells from the patient.
- Ship them to a company that will use them to make complexes with adjuvant materials.
- The complexes are returned to be injected into the patient.
Several of such vaccines are currently in clinical trials.
These vaccines are used to immunize the patient with an antigen universally expressed by tumors of that type (but not by normal cells) mixed with some form of adjuvant that will enhance the response.
- Many cancer patients mount an immune response — both antibody-mediated and cell-mediated — against the tumor (and testis) antigen NY-ESO-1. Deliberate immunization with this protein (plus an adjuvant) boosts this response and has shown some promise in early clinical trials. (Cells in the testis do not express HLA antigens, so are not at risk from attack by NY-ESO-1-specific cytotoxic T lymphocytes).
- MAGE-A3 is another protein common on cancer cells. A vaccine using MAGE-A3 — along with an adjuvant — is in Phase III clinical trials to assess its effectiveness against melanoma and lung cancer.
- HER2 is a protein over-expressed on 20–30% of breast cancers. NeuVax® is a vaccine that contains a peptide of HER2 along with recombinant GM-CSF as an adjuvant. It stimulates the formation of cytotoxic T lymphocytes (CTLs) that attack cells expressing HER2 and has shown promise in clinical trials.
Unlike patient-specific vaccines, these vaccines can be mass-produced for use in anyone with the appropriate tumor.
Combining Procedures #3 and #4
While tumors are immunogenic in the patient who carries them, they are only weakly so. In the hopes of improving cancer immunotherapy, clinical trials are now proceeding to test the efficacy of combining potent patient-specific cancer immunization with treating the patient with large numbers of cultured cancer-antigen-specific T cells that result.
The patient is repeatedly immunized with his or her own cancer cells along with a strong adjuvant (e.g., GM-CSF) followed by harvesting the patient's leukocytes and growing large numbers of them in the laboratory before infusing them into the patient along with interleukin-2. This combined approach — which generates large numbers of patient-cancer-specific killer T cells — has been tested against kidney and one type of brain cancer with promising results.
Cancers of blood cells, leukemias and lymphomas, arise in the bone marrow — the source of all blood cells.
One approach to curing leukemia is to treat the patient with such high doses of chemotherapy and radiation that not only are the leukemic cells killed, but the patient's bone marrow is destroyed. If the patient is to survive the treatment, called "myeloablative conditioning", he or she must be given a transplant of hematopoietic stem cells — the cells from which all blood cells are formed.
The stem cells can be
- an autograft; that is, from bone marrow harvested from the patient and stored before treatment begins. In this case, however, the marrow must also be treated to purge it of all cancer cells it may contain before it is returned to the patient. This sometimes fails.
- an allograft; that is, cells harvested from another person, usually a family member sharing the same major histocompatibility molecules.
Allografted hematopoietic stem cells also sometimes fail to cure, but in that case it is because not all of the patient's leukemic cells were destroyed. However, an infusion of T lymphocytes from the blood of the same donor that provided the cells can finish off the job.
This effect is called the graft-versus-leukemia effect.
However, most (if not all) of the donor T cells are probably attacking normal cell surface molecules, not tumor-specific ones. (Even if the donor and recipient are matched for the major histocompatibility molecules, there will be minor ones that elicit a rejection response.)
So the patient may also suffer life-threatening graft-versus-host disease (GVHD).
The graft-versus-leukemia effect lays the foundation for an approach that has shown considerable promise against various blood cancers and even some solid (e.g., kidney) tumors.
- The patient is treated to kill some — but not all — of the bone marrow cells (nonmyeloablative conditioning).
- Instead of using high doses of radiation to the entire body and chemotherapy, only the lymphoid organs (spleen, thymus, lymph nodes) are irradiated (called "total lymphoid irradiation").
- Antithymocyte globulin can also be given.
- Even though this leaves some cancer cells, it makes it possible for allogeneic bone marrow stem cells to take up long-term residence in the recipient (just as immunosuppression allows kidney transplants, etc. to avoid rejection by the recipient).
- This is followed by an infusion of T cells from the same donor. These can then go to work against the cancer cells without being threatened with rejection by the host.
- Once again, though, they will also attack normal cells of the recipient usually causing graft-versus-host disease (GVHD). However, this promises to be milder than that following myeloablative conditioning — perhaps because repeated small doses of radiation favors the survival of natural killer (NK) cells, and these appear to protect against GVHD.
In mice, the graft-versus-leukemia effect can be enjoyed without the downside of GVHD by including extra-large numbers of regulatory T cells (Treg cells) in the bone marrow infusion. Whether this approach could be helpful for humans remains to be seen.
It has long been known that viral infections can occasionally (and unpredictably) cause tumors to regress. A number of viruses have been studied in the hope of developing a reliable therapy. On 27 October 2015, the U.S. FDA approved T-VEC (Imlygic®) for the treatment of melanoma. T-VEC is a mutated and engineered Herpes Simplex Virus (HSV-1 — the cause of cold sores). The alterations in the virus include incorporating the gene for GM-CSF and a mutation that prevents the virus from infecting non-dividing cells while preserving its ability to infect and replicate in cancer cells. Replication kills the cells and causes them to release:
- more viruses which spread the infection;
- tumor antigens, and
- GM-CSF which attracts dendritic cells to the site. These take up the tumor antigens and present them to T cells that go on to mount an attack against surviving tumor cells.
(Tumor cell death by HSV does not qualify it as immunotherapy, but the T-cell response that results certainly does.)
Two Drugs Are Better Than One
Immune checkpoint inhibitor combinations have already proven to be more effective than single agents in several cancers. For example, studies have shown that treatment with nivolumab and ipilimumab (Yervoy), which blocks an immune checkpoint protein known as CTLA-4, is more effective than nivolumab alone for melanoma that has spread to the brain.
Other studies have shown a similar benefit to combining immune checkpoint inhibitors for people with advanced non-small cell lung cancer. But the improved outcomes have generally come at the cost of more serious, and more frequent, side effects. Researchers have begun looking at other combinations to see if these can result in the same or better cancer-specific results, but with fewer side effects.
In the RELATIVITY-047 trial, 714 patients with previously untreated advanced melanoma were randomly assigned to receive either nivolumab plus relatlimab or nivolumab alone. Both drugs are given intravenously.
One year after beginning treatment, approximately 48% of patients who received both immunotherapy drugs were alive without their cancer getting worse, compared with 36% of patients treated with nivolumab alone.
Of the patients receiving nivolumab and relatlimab, 18.9% had serious side effects, including fatigue, rash, aching or painful joints, and diarrhea, compared with 9.7% of patients treated with nivolumab alone. The adverse events led 14.6% of the patients in the nivolumab and relatlimab group to stop treatment, compared with 6.7% of patients in the nivolumab alone group.
Comparing the combination of nivolumab and relatlimab with the combination of nivolumab and ipilimumab, “I think the big differentiator is in the reduced toxicities,” said Dario A. Vignali, Ph.D., who co-leads the Cancer Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center Hillman Cancer Center.
The severe side effects associated with the combination of nivolumab and relatlimab are “way lower” than the severe side effects associated with the combination of nivolumab and ipilimumab, Dr. Vignali noted.
“Toxicities can be quite intolerable for a lot of patients, which reduces their quality of life. A third of patients [who receive] nivolumab plus ipilimumab have to discontinue treatment at some point, and that gives them very few [treatment] options,” said Dr. Vignali. “I think that [the] reduced toxicity is a game changer in many ways.”
Dr. Vignali was not involved in the RELATIVITY-047 trial but has served as a consultant to Bristol Myers Squibb, the company that developed relatlimab and funded the clinical trial.
Dr. Chandra agreed, saying that having a combination with fewer severe side effects “can really be practice changing.”
Immunotherapy to Treat Cancer
Immunotherapy is a type of cancer treatment that helps your immune system fight cancer. The immune system helps your body fight infections and other diseases. It is made up of white blood cells and organs and tissues of the lymph system.
Immunotherapy is a type of biological therapy. Biological therapy is a type of treatment that uses substances made from living organisms to treat cancer.
How does immunotherapy work against cancer?
Immunotherapy: How the Immune System Fights Cancer
Immunotherapy: How the Immune System Fights Cancer
Learn about nonspecific immune stimulation, T-cell transfer therapy, and immune checkpoint inhibitors, which are 3 types of immunotherapy used to treat cancer.
As part of its normal function, the immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers. For instance, immune cells are sometimes found in and around tumors. These cells, called tumor-infiltrating lymphocytes or TILs, are a sign that the immune system is responding to the tumor. People whose tumors contain TILs often do better than people whose tumors don’t contain them.
Even though the immune system can prevent or slow cancer growth, cancer cells have ways to avoid destruction by the immune system. For example, cancer cells may:
- Have genetic changes that make them less visible to the immune system.
- Have proteins on their surface that turn off immune cells.
- Change the normal cells around the tumor so they interfere with how the immune system responds to the cancer cells.
Immunotherapy helps the immune system to better act against cancer.
What are the types of immunotherapy?
Several types of immunotherapy are used to treat cancer. These include:
- Immune checkpoint inhibitors, which are drugs that block immune checkpoints. These checkpoints are a normal part of the immune system and keep immune responses from being too strong. By blocking them, these drugs allow immune cells to respond more strongly to cancer.
T-cell transfer therapy may also be called adoptive cell therapy, adoptive immunotherapy, or immune cell therapy.
Monoclonal antibodies may also be called therapeutic antibodies.
Which cancers are treated with immunotherapy?
Immunotherapy drugs have been approved to treat many types of cancer. However, immunotherapy is not yet as widely used as surgery, chemotherapy, or radiation therapy. To learn about whether immunotherapy may be used to treat your cancer, see the PDQ® adult cancer treatment summaries and childhood cancer treatment summaries.
What are the side effects of immunotherapy?
Immunotherapy can cause side effects, many of which happen when the immune system that has been revved-up to act against the cancer also acts against healthy cells and tissues in your body.
How is immunotherapy given?
Different forms of immunotherapy may be given in different ways. These include:
- Intravenous (IV)
The immunotherapy goes directly into a vein.
The immunotherapy comes in pills or capsules that you swallow.
The immunotherapy comes in a cream that you rub onto your skin. This type of immunotherapy can be used for very early skin cancer.
The immunotherapy goes directly into the bladder.
Where do you go for immunotherapy?
You may receive immunotherapy in a doctor’s office, clinic, or outpatient unit in a hospital. Outpatient means you do not spend the night in the hospital.
How often do you receive immunotherapy?
How often and how long you receive immunotherapy depends on:
- Your type of cancer and how advanced it is
- The type of immunotherapy you get
- How your body reacts to treatment
You may have treatment every day, week, or month. Some types of immunotherapy given in cycles. A cycle is a period of treatment followed by a period of rest. The rest period gives your body a chance to recover, respond to the immunotherapy, and build new healthy cells.
How can you tell if immunotherapy is working?
You will see your doctor often. He or she will give you physical exams and ask you how you feel. You will have medical tests, such as blood tests and different types of scans. These tests will measure the size of your tumor and look for changes in your blood work.
What is the current research in immunotherapy?
NCI’s Role in Immunotherapy Research
NCI supports a wide range of immunotherapy research, from basic science to clinical trials.
Researchers are focusing on several major areas to improve immunotherapy, including:
- Finding solutions for resistance.
Researchers are testing combinations of immune checkpoint inhibitors and other types of immunotherapy, targeted therapy, and radiation therapy to overcome resistance to immunotherapy.
- Finding ways to predict responses to immunotherapy.
Only a small portion of people who receive immunotherapy will respond to the treatment. Finding ways to predict which people will respond to treatment is a major area of research.
- Learning more about how cancer cells evade or suppress immune responses against them.
A better understanding of how cancer cells get around the immune system could lead to the development of new drugs that block those processes.
- How to reduce the side effects of treatment with immunotherapy.
How do you find clinical trials that are testing immunotherapy?
To find clinical research studies that involve immunotherapy visit Find NCI-Supported Clinical Trials or call the Cancer Information Service, NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
NCI’s list of cancer clinical trials includes all NCI-supported clinical trials that are taking place across the United States and Canada, including the NIH Clinical Center in Bethesda, MD.
Immunotherapy in Small Cell Lung Cancer
Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the cornerstone of treatment for patients with extensive disease, but there has been no real progress for 30 years. The evidence that SCLC is characterized by a high mutational burden led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy. Randomized phase III trials demonstrated that the combination of atezolizumab (IMpower-133) or durvalumab (CASPIAN) with platinum-etoposide chemotherapy improved overall survival of patients with extensive disease. Instead, the KEYNOTE-604 study demonstrated that the addition of pembrolizumab to chemotherapy failed to significantly improve overall survival, but it prolonged progression-free survival. The safety profile of these combinations was similar with the known safety profiles of all single agents and no new adverse events were observed. Nivolumab and pembrolizumab single agents showed anti-tumor activity and acceptable safety profile in Checkmate 032 and KEYNOTE 028/158 trials, respectively, in patients with SCLC after platinum-based therapy and at least one prior line of therapy. Future challenges are the identification predictive biomarkers of response to immunotherapy in SCLC and the definition of the role of immunotherapy in patients with limited stage SCLC, in combination with radiotherapy or with other biological agents.
Keywords: PDL-1 SCLC atezolizumab durvalumab ipilimumab nivolumab pembrolizumab tremelimumab tumour mutation burden.
Conflict of interest statement
Alessandro Morabito declares the following conflicts of interest: Speaker’s fee: MSD, BMS, Boehringer, Pfizer, Roche, AstraZeneca Advisory Board: Takeda. Nicola Normanno declares the following personal financial interests (speaker’s fee and/or advisory boards): MSD, Qiagen, Bayer, Biocartis, Incyte, Roche, BMS, MERCK, Thermofisher, Boehringer Ingelheim, Astrazeneca, Sanofi, Eli Lilly Institutional financial interests (financial support to research projets) : MERCK, Sysmex, Thermofisher, QIAGEN, Roche, Astrazeneca, Biocartis. Non-financial interests: President, International Quality Network for Pathology (IQN Path) President, Italian Cancer Society (SIC). All the other Author declare no conflict of interest.
Dendritic cell biology and its role in tumor immunotherapy
As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and sequences, and (3) present MHC-peptides to CD4 + and CD8 + T cells to initiate immune responses against invading microbes and aberrant host cells. During anti-tumor immune responses, DC-derived exosomes were discovered to participate in antigen presentation. T cell microvillar dynamics and TCR conformational changes were demonstrated upon DC antigen presentation. Caspase-11-driven hyperactive DCs were recently reported to convert effectors into memory T cells. DCs were also reported to crosstalk with NK cells. Additionally, DCs are the most important sentinel cells for immune surveillance in the tumor microenvironment. Alongside DC biology, we review the latest developments for DC-based tumor immunotherapy in preclinical studies and clinical trials. Personalized DC vaccine-induced T cell immunity, which targets tumor-specific antigens, has been demonstrated to be a promising form of tumor immunotherapy in patients with melanoma. Importantly, allogeneic-IgG-loaded and HLA-restricted neoantigen DC vaccines were discovered to have robust anti-tumor effects in mice. Our comprehensive review of DC biology and its role in tumor immunotherapy aids in the understanding of DCs as the mentors of T cells and as novel tumor immunotherapy cells with immense potential.
Keywords: Dendritic cells (DCs) Immune cells MHC Tumor immunotherapy.
Conflict of interest statement
The authors declare that they have no conflict of interest relating to the publication of this manuscript.
Ratings and Reviews
Professor, Dept of Human & Molecular Genetics, Virginia Commonwealth University, USA Associate Director, VCU Institute of Molecular Medicine, Virginia, USA. The Wang laboratory has a long-standing interest in understanding stress response and stress sensing molecules in regulation of inflammation, host immunity, and the pathogenesis of diseases, including cancer.
Affiliations and Expertise
Institute of Molecular Medicine, Virginia Commonwealth University, USA
Paul B. Fisher, MPh, PhD, FNAI, Professor and Chairman, Department of Human and Molecular Genetics, Director, VCU Institute of Molecular Medicine Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center, VCU, School of Medicine, Richmond, VA, and Emeritus Professor, Columbia University, College of Physicians & Surgeons, New York, NY. Dr. Fisher is among the top 10% of NIH funded investigators over the past 35-years, published approximately 625 papers and reviews, and has 55 issued patents. He pioneered novel gene/discovery approaches (subtraction hybridization), developed innovative therapeutic approaches (Cancer Terminator Viruses), presented numerous named and distinguished lectures, founded several start-up companies, was Virginia Outstanding Scientist of 2014 and elected to the National Academy of Inventors in 2018. Dr. Fisher is a prominent nationally and internationally recognized cancer research scientist focusing on understanding the molecular and biochemical basis of cancer development and progression to metastasis and using this garnered information to develop innovative approaches for diagnosing and treating cancer. He discovered and patented novel genes and gene promoters relevant to cancer growth control, differentiation and apoptosis. His discoveries include the first cloning of p21 (CDK inhibitor), human polynucleotide phosphorylase, mda-9/syntenin (a pro-metastatic gene), mda-5 and mda-7/IL-24, which has shown promising clinical activity in Phase I/II clinical trials in patients with advanced cancers. Dr. Fisher alsohas a documented track record as a successful seasoned entrepreneur. He was Founder and Director of GenQuest Incorporated, a functional genomics company, which merged with Corixa Corporation in 1998, traded on NASDAQ and was acquired by GlaxoSmithKline in 2006. He discovered the cancer-specific PEG-Prom, which is the core technology of Cancer Targeting Systems (CTS, Inc.), a Virginia/Maryland-based company (at Johns Hopkins Medical Center) focusing on imaging and therapy (“theranostics”) of metastatic cancer (2014) by Drs. Fisher and Martin G. Pomper. He co-founded InVaMet Therapeutics (IVMT) and InterLeukin Combinatorial Therapies (ILCT) with Dr. Webster K. Cavenee (UCSD) (2017/2018).
Affiliations and Expertise
Institute of Molecular Medicine, Virginia Commonwealth University, VA, USA
Monday March 30, 2020
- 8:30-9:00 Welcome and Introductions
- Dr. Wayne C. Glasgow, Senior Vice Provost for Research, Mercer University
- Dr. J. David Baxter, Senior Associate Dean Savannah, Mercer University School of Medicine
- Dr. Michael G. Hanna Jr., Per-Immune Inc., Savannah, GA
- Plenary Session 1: Cancer biology, pathology and metastasis
- 9:00-9:40 Dr. Julie Magarian Blander, Cornell University, New York, NY
- Innate immunity in immunotherapy, macrophages and dendritic cells
- 9:40-10:20 Dr. J J O’leary, Trinity College, Dublin, Ireland
- Cancer pathology and tumor growth kinetics, metastasis and tumor cell-stroma relationships
- 10:20-11:00 Dr. Heyu Ni, University of Toronto, Toronto, Canada
- The roles of blood platelets in cancer: immune response, metastasis and cancer-related thrombosis
- 11:00-11:20Coffee Break
- 11:20-12:00 Dr. Michael Hwang, Johns Hopkins Medical Institute, Baltimore, MD
- Mutations in oncogenes and tumor suppressor genes drive tumorigenesis: MANA bodies TCR-mimic antibodies for cancer therapy
- 12:00-12:40 Dr. Joshua L. Hood, University of Louisville, KY
- Exploring tumor exosome induction of macrophage polarity and therapeutic potential in the context of immune suppression
- 12:40-01:00 Panel Discussion
- 1:00-2:00 Lunch
- Plenary Session 2: Passive immunotherapy
- Moderator: Dr. Jason David Howard, Sanofi-Genzyme, Cambridge, MA
- 2:00-2:40 Dr. Jason David Howard, Sanofi-Genzyme, Cambridge, MA
- Passive immunotherapy in advanced disease cancer patients
- 2:40-3:20 Dr. Christopher E. Rudd, University of Montreal, Quebec, Canada
- GSK-3 Inactivation synergizes with PD-1/PL1 and CTLA-4 blockade in cancer immunotherapy
- 3:20-3:50Coffee Break
- 3:50-4:30 Dr. Keith Knutson, Mayo Clinic, Jacksonville, FL
- Immunotherapy beyond checkpoint
- 4:30-5:10 Dr. Michael Lotze, UPMC Hillman Cancer Center, Pittsburgh, PA
- Adoptive cell therapies for cancer: focus on tumor infiltrating lymphocytes
- 5:10-5:50 Dr. Ugo Rovigatti, University of Florence, Italy
- From anti-GD2 passive immunotherapy in High-Risk Neuroblastoma (HR-NBL) to a new landscape of genomic aberrations and immunotherapy targets
- 5:50-6:30 Panel discussion
Tuesday March 31, 2020
- Plenary Session 3: Cancer immunoprevention
- 8:30-9:10 Dr. Hideho Okada, University of California San Francisco, CA
- Vaccine approaches for patients with low-grade glioma aimed at prevention of malignant transformation
- 9:10-9:50 Dr. Vincent K. Tuohy, Cleveland Clinic, Lerner Institute, Cleveland Ohio
- Primary immunoprevention of adult onset cancers
- 9:50-10:30 Coffee Break
- 10:30-11:10 Dr. Olivera Finn, University of Pittsburgh, Pittsburgh, PA
- Vaccines for the prevention of non-viral cancers
- 11:10-12:00 Panel discussion
- 12:00-1:00 Lunch
- Plenary Session 4: Active specific immunotherapy
- Moderator: Dr. Robert Dillman, AIVITA Biomedical, Irvine, CA
- 1:00-1:40 Dr. Robert Dillman, AIVITA Biomedical, Irvine, CA
- Evolution of therapeutic cancer vaccines
- 1:40-2:20 Dr. Michael G. Hanna Jr., Per-Immune Inc., Savannah, GA
- Unlocking The Potential of Personal Cancer Vaccines: The Clinical Ramifications of Antigen Competition Driven Immunoediting
- 2:20-2:50Coffee Break
- 2:50-3:30 Dr. J. Milburn Jessup, Veterans Administration Medical Center, Washington, DC
- Immunogenic cell death is an agnostic adaptive immunity primer for solid tumors
- 3:30-4:10 Dr. F. Guirakhoo, GeoVax Inc. Atlanta, GA
- MVA-VLP as a safe and effective platform for delivery of multi-antigen vaccine candidates for infectious diseases and cancer
- 4:10-5:00 Panel Discussion
Wednesday April 1, 2020
- Plenary Session 5: Cancer immunotherapy monitoring, methodology and drug design
- Moderator: Dr. Peter Nara, Keystone Bio Inc., St. Louise, MO
- 8:30-9:10 Dr. Peter Nara, Keystone Bio Inc., St. Louise, MO
- Cancer treatment monitoring and drug design
- 9:10-9:40 Dr. Richard G. Pestell, Pennsylvania Cancer and Regenerative Medicine Center, PA
- Cancer Stem cells (CSC). Genetic drivers and therapeutic targeting via a new receptor
- 9:40-10:10 Dr. Martin D’Souza, School of Pharmacy, Mercer Medical School, Atlanta, GA
- Cancer nano-vaccines delivered via “Band-Aid Like” microneedle patches
- 10:10-10:30 Coffee Break
- 10:30-11:00 Dr. Joanna Roder, Biodesix, Boulder, CO
- Application of machine learning to proteomic datasets: What can AI tell us about immune phenotypes from measurements of the circulating proteome?
- 11:00-11:30 Dr. Karen A. Norris, University of Georgia, Athens, GA
- Immunity and immunization in the immunocompromised host
- 11:30-12:00 Dr. Pavan Muttil, The University of New Mexico, Albuquerque, NM
- A pulmonary delivery approach to administer combination therapies against lung cancer: are animal models a bane or a boon?
- 12:00-12:30 Panel Discussion
- 12:30-1:30 Lunch and Meeting Closure
Cancer Biology PhD Program
The GW Cancer Biology PhD program is designed to equip the next generation of researchers with the knowledge, research training and leadership skills necessary to foster progress in the prevention, detection and treatment of cancer.
The establishment of the GW Cancer Center (GWCC) in late 2015 brought together cancer research, clinical cancer care, and cancer control/prevention and outreach initiatives at GW. Simultaneously with the formation of GWCC, the University opened a $275M state-of-the-art, 500,000 square foot Science and Engineering Hall, the top floor of which hosts many investigators in the GWCC.
The Cancer Biology PhD program provides research training areas reflecting GW faculty expertise, which includes the study of cancer genomics, cancer immunology and immunotherapy, and molecular mechanisms of oncogenesis and metastasis, cancer signaling and genomics, cancer epigenetics & technology, tumor immunology, epigenetic changes, chemotherapy, signaling and checkpoint inhibitors, tumor microenvironment, cancer genetics and genomics. An important focus for the Cancer Center is to address prominent health disparities in breast, cervical, colorectal, pancreatic, liver and prostate cancers faced by communities in the District of Columbia.
PhD programs in the biomedical sciences are designed to meet key goals in contemporary graduate research education including 1) discipline-specific knowledge, 2) research skill development, 3) research communication skills, 4) research leadership and 5) research professionalism and prepare graduates for a variety of science careers. To apply, please visit IBS Admissions .
Students have access to cutting-edge core facilities for flow cytometry, imaging, and computational biology as well as the state of the art George Washington Biorepository resource of biospecimens and clinical data designed to help today's leading investigators facilitate their research on HIV/AIDS and cancer.
The PhD in Cancer Biology begins with interdisciplinary coursework in molecular, cellular, and systems biology in the first semester. In the second and third semester students take a comprehensive introduction to the conceptual and experimental underpinnings of Cancer Biology. Career development coursework in scientific writing, oral communication, and research ethics and laboratory rotations offered through GW’s Institute for Biomedical Sciences curriculum . Following required laboratory rotations, students work with their research advisor and the Graduate Program Directors to complete remaining Cancer Biology degree requirements, including the dissertation.
BMSC 8210: Genes to Cells
BMSC 8212: Systems Physiology
BMSC 8230: Molecular Basis of Human Disease
BMSC 8215: Laboratory Rotations (3)
BMSC 8216: Career Skills: Scientific Writing and Speaking
BMSC 8217: Career Skills: Ethics and Grantsmanship
One or more Foundation Course(s):
Basic Science of Cancer Biology
Infection and Immunity
Genomics, Proteomics and Bioinformatics
Neural Cells and Circuits
Pharmacogenomics and Personalized Medicine
BMSC 8219: Career Skills: Biomedical Science Careers
BMSC 8235: Applied Biostatistics for Basic Research
Complete grant-style qualifier examination, advance to candidacy
Cancer Biology Core:
CANC 8221: The Basic Science of Oncology
CANC 8222: Molecular Oncology and Epigenetics
CANC 8224: Clinical Oncology. Basic science behind the treatment of patients
CANC 8998: Advanced Reading and Research Seminar Course
CANC 8999: Dissertation Research
Some Suggested Electives:
GENO 6237: Proteomics & Biomarkers
CANC 8223: Cancer Immunology Cancer immunology, checkpoint inhibitors, CAR-T cell therapy, adoptive immunity
BIOC 6240: Next Gen Sequencing Basic principles of NGS technologies, data analysis and interpretation. Research and clinical applications and student-designed projects
HSCI 6263: Biostatistics Clinical Translational Scientific Research Basic concepts and methods of biostatistics applied to translational research. Topics include distributions, populations and sample selection, variables, interaction and confounding, hypothesis formulation, correlation, t-tests, ANOVA, regression (online)
The Cancer Biology seminar series held is held Thursday at 4 pm, and the monthly Tumor Board discussions held each Friday morning at 8 am. An annual Cancer Center Retreat is held in May. Faculty and trainees share interest groups (breast, prostate, ovarian cancer) as well as thematic meetings (Cancer Biology, Cancer Immunology, Cancer Engineering), to focus on common research interests.
Graduate Program Director:
Norman Lee, PhD
Professor of Pharmacology & Physiology
GWU Ross Hall 601
Yanfen Hu, PhD
Professor of Anatomy & Cell Biology
GWU Ross Hall 551-B
How to apply to the IBS and Cancer Biology PhD program
For IBS Application Questions contact Colleen Kennedy, IBS Program Manager
'Suffocating' cancer: A new headway in melanoma immunotherapy
Hypoxia, or the inadequate oxygenation of a tissue, is a condition occurring frequently in all solid tumours such as melanoma skin cancer. Melanoma cells are not only able to survive oxygen deprivation, but also to use it to their own advantage by hijacking the anti-tumour immune response and developing resistance mechanisms to conventional anti-cancer therapies. A key gene responsible for cancer cell adaptation to hypoxia is HIF-1α (Hypoxia Inducible Factor-1 alpha). Led by Dr Bassam Janji, head of the Tumor Immunotherapy and Microenvironment (TIME) research group at the Luxembourg Institute of Health (LIH) and in collaboration with Gustave Roussy Cancer Center in France and the Thumbay Research Institute of Precision Medicine at Gulf Medical University in the United Arab Emirates, the team used gene editing technologies to show how targeting HIF-1α could not only inhibit tumour growth, but also drive cytotoxic (toxic to cells) immune cells to the cancer tissue. This discovery provided a valuable new target to make resistant melanomas more vulnerable to available anti-cancer treatments. Their findings were recently published in the reputable Oncogene Journal.
Melanoma is a type of skin cancer that develops from melanocytes, cells that are responsible for the production of pigments. Melanomas become harder to treat if not detected early, with emerging treatment resistance being an important barrier to their effective management. Due to their rapid growth rate and low blood supply, solid tumours including melanoma often exhibit areas of hypoxia. Hypoxia, or the decrease of oxygen in the tumour microenvironment, would normally cause tumour cell death. "However, certain solid tumours have evolved to survive this hostile microenvironment by activating HIF-1α, a gene reported to be a major factor mediating the adaptive response to changes in tissue oxygen level," explains Dr Janji. William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza were awarded the Nobel Prize in Physiology or Medicine in 2019 for their discovery of HIF-1? and how cells use it to sense hypoxia. Hypoxia has also been reported to be responsible for the failure of tumour response to conventional anti-cancer therapies and can prevent the infiltration of immune cells into the tumour. It is therefore crucial to understand the mechanisms by which cancer cells overcome this hypoxic environment to improve the effectiveness of available anti-cancer therapies.
In this context, the team led by Dr Janji sought to inactivate the functionality of the HIF-1α gene using CRISPR gene editing technology and investigate the impact of such inactivation on tumour growth, immune cell infiltration and response to immunotherapy in a preclinical melanoma mouse model.
"Our study revealed that blocking the activity of HIF-1α significantly inhibited melanoma growth and amplified the infiltration of immune cells into the tumour microenvironment by increasing the release of CCL5, a well-defined mediator involved in driving cytotoxic immune cells to the tumour battlefield", summarises Dr Audrey Lequeux, first author of the publication. Importantly, the study also showed that combining a drug devised to stop hypoxia significantly improves melanoma immunotherapy. When the results were validated retrospectively in a cohort of 473 melanoma patients, the hypoxic signature of tumours was correlated to worsened outcomes and the lack of immune cell infiltration into tumours, which is considered as a major characteristic of tumour resistance to immunotherapies.
"Together, our data strongly argue that therapeutic strategies disrupting HIF-1α would be able to modulate the tumour microenvironment to permit the infiltration of immune cells. Such strategies could be used to improve vaccine-based and immune checkpoint blockade-based cancer immunotherapies in non-responder melanoma patients," conclude Dr Chouaib and Dr Janji from Gulf Medical University and Luxembourg Institute of Health, respectively.
The study was published in June in the Oncogene journal, part of the prestigious Nature publishing group, with the full title "Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy". The article was listed under the category of 'brief communication', a category reserved for articles of exceptional interest due to their significance and timely contribution to cancer biology.
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