Affordable Access

Publisher Website

Combination immunotherapy of cancer

Elsevier Science & Technology
DOI: 10.1016/s1567-7443(01)80039-9
  • Biology
  • Medicine


Abstract The interaction of cancer with the immune system has long been established. Modernapproaches to cancer immunotherapy concentrate on boosting host resistance by vaccines, killer cells or cytokines, such as interleukin-2 or interferons. Little attention has been paid to the possibility of sensitizing tumor cells to immune mediated attack. The non-steroidal antiestrogenic agents, tamoxifen (TX) and toremifene (TO) are widely used for the treatment of estrogen receptor positive mammary carcinomas and other sex hormone dependent tumors. We discovered that TX and TO sensitize tumor cells for killing by natural killer (NK), lymphokine activated killer (LAK) and cytotoxic T lymphocytes (CTL). We also demonstrated that TX and TO potentiated the immunotherapy of lethal cancer in syngeneic murine tumor-host system. DBA/2 and C3H mice were injected with lethal doses of tumor cells subcutaneously. Combination therapy with NK, LAK or CTL effector cells and antiestrogens could cure lethal cancer in up to 75% of mice. Lymphocytes freshly isolated from the ascites of patients with ovarian cancer had no lytic effect on autologous tumor cells. Activation of tumor associated lymphocytes (TAL) or tumor infiltrating lymphocytes (TIL) with hrIL-2 in the presence of autologous tumor cells induced detectable cytotoxicity in most of the cell cultures. A highly significant increase of tumor cell lysis was found when both target and effector cells were treated with antiestrogens. Additional treatment with interferon-alpha resulted in the further enhancement of cytotoxicity in a significant number of cases. It is clear from our results that TX and TO are capable of increasing the susceptibility ofhuman ovarian and lung cancer cells to autologous killer cells in about 60% of the cases so examined. Sensitization requires the active metabolic participation of the target cells suggesting the amplification of programmed cell death as the underlying mechanism. Both the Fas/Fas-L and perforin/granzyme pathways, which can trigger apoptosis, are affected by antiestrogens. This was further supported by the observations that Fas receptor expression on ovarian carcinoma cells and the Fas-antibody mediated killing of ovarian carcinomas were upregulated by antiestrogen treatment. In contrast, TX and TO did not stimulate the Fas-L expression on killer cells. The lack of correlation between Fas receptor expresion and drug induced increase of kille cell mediated cytolysis suggest the participation of the perforin/granzyme pathway. K562 cells are Fas negative and are not susceptible to anti-Fas mediated cytolysis. However, antiestrogen treatment significantly inceased the NK cell mediated cytotoxicity of K562 cells. The total abrogation of cell death by chelation of extracellular Ca++ indicates that NK cell mediated cytolysis of K562 cells was dependent on perforin/grenzyme pathway. Similar results were obtained with the Fas receptor positive ovarian carcinomas. It is clear from our results that antiestrogens reder the cancer cells more susceptible forkiller cell mediated destruction, and thereby potentiate immune defence against cancer. On the basis of our combination immunotherapy experiments in tumor bearing mice we now conduct feasibility trials for the development of treatment protocols for the combination immunotherapy of cancer in man.

There are no comments yet on this publication. Be the first to share your thoughts.


Seen <100 times

More articles like this

Immunotherapy and targeted therapy combinations in...

on Current clinical pharmacology August 2011

Immunotherapy as part of combinations for the trea...

on International Immunopharmacolo... Jan 01, 2003

Immunotherapy as part of combinations for the trea...

on International immunopharmacolo... August 2003
More articles like this..