EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells.
OBJECTIVE
Immunotoxins as anti-cancer therapeutics have several potential advantages over conventional agents including a high specificity, extraordinary potency, and a lack of an identified mechanism for resistance. It has been clearly demonstrated that Pseudomonas-based immunotoxins have a direct cytotoxic effect. However, delayed and often dramatic antitumor responses seen in human studies with targeted toxins led us to hypothesize that immunologic responses may be a secondary mechanism that enhances the therapeutic efficacy of these novel drugs.


METHODS
This hypothesis was tested in a murine system using an immunotoxin, MR1-1 [MR1-1(dsFv)-PE38KDEL], that targets a syngeneic murine homologue of the tumor-specific human epidermal growth factor mutation, EGFRvIII, expressed on a murine cell line.


RESULTS
Intratumoral treatment with MR1-1 eliminated EGFRvIII-expressing tumors (P < 0.0001). The antitumor activity of MR1-1 was dependent on the expression of EGFRvIII on some, but not all tumors cells, and was significantly inhibited in the absence of CD4+ (P = 0.0193) and CD8+ (P = 0.0193) T cells. MR1-1 induced EGFRvIII-specific immunity (P < 0.0005) and produced long lasting immunity against tumors expressing EGFRvIII as well as EGFRvIII-negative tumors.


CONCLUSIONS
These data suggest that immunotoxins may not be strictly dependent on direct cytotoxicity for their efficacy, but may also be potent inducers of antitumor immunity active even against cells that do not express the targeted antigen.
Ochiai
Hidenobu
H
Department of Surgery (Neurosurgery), Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.
Archer
Gary E
GE
Herndon
James E
JE
Kuan
Chien-Tsun
CT
Mitchell
Duane A
DA
Bigner
Darell D
DD
Pastan
Ira H
IH
Sampson
John H
JH
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*
D000970:Antineoplastic Agents; D000922:Immunotoxins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors