Cancer Immunotherapy includes a broad range of therapies aimed at eliciting an effective immune response against the cancerous cells of the host.  Strategies behind cancer immunotherapy are varied, as attempts have been made to stimulate both non-specific and specific immunity, and induce both the humoral and cellular responses.  These attempts have taken many forms, including recombinant viruses and bacteria, cytokine therapy, passive transfer of specific antibodies, gene therapy, and adoptive transfer of effector cells.  Briefly will be described immunotherapies for cancer in general.
 
 

Active immune response therapies attempt to stimulate the host immune system to mount an effector response against cancerous cells in the host

Non Specific Stimulation of the Immune System-  Nonspecific immune stimulation of cancer patients with adjuvants such as BCG has been tried for many years.  Typically, the adjuvant would be injected at the site of the tumor in hopes of activating macrophages and promoting macrophage-mediated tumor cell killing.  Oncologists are still assesing the use of BCG in some carcinomas and melanomas.  An experimental approach to nonspecific immune stimulation is the administration of low doses of anti-CD3 antibodies, which would result in polyclonal activation of T cells.  Treatments with cytokines also constitute a method of enhancing the immune response in a nonspecific manner.

Whole Killed Cell Vaccinations- Protective immunity could theoretically be induced by injecting cells expressing these antigens with an adjuvant into the patient in hopes of elliciting a lymphocyte mediated immune response.  Unfortunately, whole killed cell vaccines have not been very successful in activating a specific CTL response.

Tumor Antigen Vaccinations- Vaccination with an immunogenic Tumor Associated Antigen (TAA) preparation could lead to a tumor specific CTL response.  Immunization with these antigens could be accomplished by direct injection of purified peptide from recombinent cells expressing the antigen or expression vectors coding for the tumor antigens (DNA Vaccine).

Cytokine Treatment-  Since tumor cells usually do not express MHC II and costimulators, they usually do not activate helper T cells and no immune response ensues.  Approaches have been proposed to by-pass the need for helper T cells by providing cytokines for T cell growth and activation.  One method uses biodegradable microspheres to release encapsulated cytokines over a long period of time.  Another method involves transfecting autologous or allogeneic tumor cells with genes coding for cytokines and injecting them into patients.  Some cytokines also possess the ability to trigger a nonspecific inflamatory response which itself possesses anti-tumor activity.  Many clinical trials employing cytokines are currently underway.

*An interesting finding in using transfected tumor cells expressing cytokines in animal models is that specific T cell immunity to these transfected tumor cells imparted immunity to these animals in subsequent challenges of non-transfected tumor cells of the same type.  This was noticed mostly for transfected cells expressing GM-CSF and likely demonstrates GM-CSF's ability to differentiate immature dendretic cells into mature APCs.

Cellular Adoptive Transfer-  Cellular adoptive transfer is the transfer of immune cells that have anti-tumor activity into a tumor bearing patient. Two variations of this approach are being tested in clinical trials.

Lymphokine-Activated Killer cell (LAK) transfer involves removing patient peripheral blood leukocytes and culturing them in vitro with IL-2 to generate LAK cells.  The LAK cells are then injected back into the patient.  Adoptive therapy with autologous LAK cells, in conjunciton with in vivo adminisration of IL-2 or other chemotherapeutic drugs has yielded impressive results in mice.  Adoptive LAK cell therapy in humans has so far been mostly restricted to advanced cases of metastatic tumors, and its efficacy has been variable.

Tumor Infiltrating Lymphocytes (TIL) transfer involves generating LAK cells from mononuclear cells obtained from infiltrate around the tumor after surgical resection.  This approach would hopefully yield tumor specific CTLs and NK cells.  TILs have also been transfected with cytokine genes to deliver cytokines locally, but this approach has yielded only limited success.
 

Antibody Adoptive Transfer-  There are various ways in which antibodies have been used in immunotherapy.  In addition to directing host immune cells to the specific tumor site, attempts have been made to conjugate tumor specific antibodies with anticancer drugs, toxins, or radioisotopes so the drugs can be delivered directly to the tumor site and by-pass toxicity to normal cells.  Antibodies targeting the idiotypes of B cell lymphomas has also been a strategy.

Immunotoxins can be made by conjugating toxins such as ricin or diptheria toxin,which are potent protein synthesis inhibitors, to antibodies.  The immunotoxin must be endocytosed by tumor cells and reach the appropriate intracellular site.

Researchers have also come up with heteroconjugate antibodies and bi-specific antibodies that would bind tumor cells and cytotoxic effector cells (such as CTLs and NK cells) so as to direct a cellular immune response on the tumor.  Creating an anti-CD-3-anti-tumor-antibody could not only bring CTLs in close contact with tumor cells, but could also activate those CTLs.

  Due to the ineffectivness of traditional cancer treatments for RCC to date, great efforts have been undertaken by researchers and clinicians alike to develop novel immunotherapies for RCC patients.
 
 

    Spontaneous regression of RCC metastases is a rare event with a frequency of approximately 0.5%.  These observations of spontaneous regression of RCC metastases have led to the conclusion that the disappearance of distant metastases without therapy may be due to rejection of the metastases by the host immune system.
 
 

* (This page was developed by undergraduate students at Brown University as a project for a course in Vaccine Development.
            The authors of this page are not certified medical professionals.  Biomedical Research and Clinical Medicine are constantly
            evolving fields, thus it is likely that significant advances in research and new treatments for Renal Cell Carcinoma have
            come into existence following the posting of this page.  To the best of our knowledge, all information presented in this
            page reflects the prevalent opinions of the field as of March 17, 2000)