Immunotherapy of colorectal cancer

Abstract

Specific and nonspecific stimulation of the host immune system to reject cancer is an attractive concept that is just beginning to mature. Results with crude extracts and nonspecific immune stimulation have been variable. However, the recent observations of improved survival after administration of levamisole plus 5‐fluorouracil in the adjuvant setting have made an impact on the treatment of colorectal cancer. Animal studies consistently show that immune therapies are most effective for disease that is not advanced. Thus, the small benefit seen with levamisole, a low toxicity immunomodulator, suggests that much more impressive results can be anticipated with more potent and specific agents. Postsurgical autologous tumor cell vaccine has been effective in some prospective randomized trials; in others, no benefit was found. The identification and purification of allogeneic tumor‐associated antigens has lead to enhanced antigen‐specific host cell‐mediated immunity; this may result in more consistent antitumor effects. The current development of chemically defined immune adjuvants of low toxicity allows tumor‐specific immune stimulation to be tested in high‐risk apparently healthy patients after resection of colorectal cancer (Stages II and III). The influx of information regarding immune cell populations, cell‐surface markers, and cytokines has fostered extensive exploration of lymphocyte stimulation, in vitro cell growth and expansion, and in vivo evaluation in patients with advanced cancer. Modest tumor response rates have been documented with adoptive transfer of lymphokine‐activated killer cells and interleukin‐2. Improved results are anticipated with the more potent tumor‐infiltrating lymphocytes and specific in vitro sensitization of draining lymph node cells to autologous and allogeneic tumor antigens. Murine monoclonal antibodies specific for cell‐surface markers, such as carcinoembryonic antigen, have been tested for their value in the diagnosis and therapy of colorectal cancer. A small response rate has been seen with single and multiple injections of C017–1A, a monoclonal antibody specific for colonic and pancreatic cancer. The development of antiidiotypic antibodies in these patients may have been important in those that responded to this type of therapy. However, laboratory evidence suggests that monoclonal antibody conjugated to a cytotoxic agent (i.e., radionuclide, drug, or toxin) should be much more effective. Radioimmunotherapy trials in the nude mouse model bearing human colon cancer xenografts showed good tumor incorporation of the radionuclide (yttrium 90 or iodine 131), inhibition of tumor growth, and long‐term survival. A combination of such therapy with (1) cytokines to enhance antigen expression and (2) cytotoxic drugs has lead to improved antitumor effects. The major hazard of radioimmunotherapy is hematologic toxicity. Bone marrow transplantation has permitted investigators to double the dose and augment the efficacy of this type of treatment. Clinical trials of radioimmunotherapy...

Design, Synthesis, Biological Evaluation and Molecular Docking Studies of 5-fluorouracil-dithiocarbamate Conjugates

“…Drug conjugates represent the several advantages to design the new anticancer agents: (1) increasing target selectivity and reducing the bystander effect [28] (eg, drug-antibody conjugates), (2) enhancing cytotoxicity and tumor targeting (eg, radionuclide-drug conjugates [29], nanoparticle-drug conjugates) and ( 3) enhancing the e cacy of anticancer therapy [30] (eg, drug-drug conjugates). To overcome low e cacy, drug resistance, and/or toxicity associated with single drug use or monotherapy, dual-drug, and even triple-drug therapies were developed or already used in clinical [31].…”