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
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, but the hope is that these can later be replaced.
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, seems to have helped some patients with kidney cancer.
- interleukin-2 (IL-2), a potent growth factor for T cells;
- alpha-interferon (IFN-α)
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.
- 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 complete remission of chronic lymphocytic leukemia (for 18 months and counting).
- 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 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.
Many such conjugates have been tried but only two have found their way into anticancer therapy.
- Mylotarg®. A conjugate of
- a monoclonal antibody that binds CD33, a cell-surface molecule expressed by the cancerous cells in acute myelogenous leukemia (AML) but not found on the normal stem cells needed to repopulate the bone marrow.
- calicheamicin, a complex oligosaccharide that makes double-stranded breaks in DNA.
Mylotarg® is the first immunotoxin to show promise in the fight against cancer.
- BL22, a conjugate of
- a monoclonal antibody against the CD22, a molecule found on the surface of some leukemias and lymphomas with
- pseudomonas exotoxin, a bacterial product [Link] that blocks protein synthesis in cells.
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)
Both are given to the lymphoma patient, the 111In version first followed by the 90Y version (in each cases supplemented with Rituxan).
- 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).
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, like cytotoxic T lymphocytes (CTL), are designed to destroy target cells. What about enlisting them in the fight?
After total destruction of the patient's own white blood cells ("myeloablative conditioning")
One approach to curing leukemia (and some other cancers) is to treat the patient with such high doses of chemotherapy and radiation that the leukemic cells are killed. Unfortunately, such high doses also destroy the patient's bone marrow. If the patient is to survive the treatment, 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).
After nonmyeloablative conditioning
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.
- 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").
- Anti-thymocyte 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 — Link).
- 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 (Tr cells) in the bone marrow infusion. Whether this approach could be helpful for humans remains to be seen.
Solid tumors contain lymphocytes that are specific for tumor antigens. 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 to date.
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.
- Reintroduce the mix of Th cells (CD4+) and CTL (CD8+) into the patient (along with IL-2).
The results:
- The infused cells usually took up longterm 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.
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.
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. [Discussion]
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).
Dendritic-cell vaccines have shown some promise against
- melanoma
- prostate cancer
- lymphoma
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.
Such vaccines are currently in clinical trials for use against chronic myelogenous leukemia (CML).
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.
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).
There is growing evidence that many cancer patients mount an immune response — both antibody-mediated and cell-mediated — against this protein. 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). [More]
Unlike patient-specific vaccines, these vaccines can be mass-produced for use in anyone with the appropriate tumor.
14 October 2005
