Index to this page
  1. Immunostimulants
  2. Cancer Therapy with Monoclonal Antibodies
  3. Cancer Therapy with T Cells
  4. Cancer Vaccines
  5. Combining Procedures #3 and #4

Cancer Immunotherapy

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.

1. Immunostimulants

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. [The evidence for immune surveillance is discussed on a separate page — link to it.] 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

2. 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).
Link to a discussion of how monoclonal antibodies are made.
Some examples:

Immunotoxins

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:

Some two dozen immunotoxins are in clinical trials. Two that have already received FDA approval:

  1. Adcetris®. A conjugate of

    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.

  2. Kadcyla® A conjugate of

    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).

Radioimmunotherapy

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:

3. Cancer Therapy with T Cells

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?

Using a Bispecific Monoclonal Antibody

Blinatumomab is a synthetic monoclonal antibody each arm of which carries a binding site with a different specificity:

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.

Allografts of T cells

After "myeloablative conditioning" (total destruction of the patient's own white blood cells)

One approach to curing leukemia (and some other cancers) 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, he or she must be given a transplant of hematopoietic stem cells — the cells from which all blood cells are formed.
Link to discussion of hematopoietic stem cell transplants.

The stem cells can be

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.

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.

Autografts of T cells: Tumor-Infiltrating Lymphocytes (TIL)

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 at that time. The procedure: The results: 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:

Autografts of a clone of 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:

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.

Gene Therapy: Autografts of genetically-modified T cells

On April 20, 2006, the Rosenberg group reported some success with melanoma patients using a modification of the TIL procedure.
See also, Monoclonal T-cell Receptors.

Another example: Chimeric Antigen Receptor (CAR) therapy

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.

4. Cancer Vaccines

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. [Discussion]

To make a dendritic-cell vaccine,

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 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.

Several of such vaccines are currently in clinical trials. An example.

Tumor-Antigen-Specific Vaccines

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.

Examples:

Unlike patient-specific vaccines, these vaccines can be mass-produced for use in anyone with the appropriate tumor.

5. 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

The procedure:

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.

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25 August 2014