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In Vivo Antitumor Activity of Anti-CD3-induced Activated Killer Cells

Office of the Director, Division of Cancer Biology and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland 20892

This study investigates the potential of the CD3-induced killer cells for use in adoptive immunotherapy of tumor growth. The CD3-induced, activated, killer cells (CD3-AK) were generated in DBA/2 (H-2^d) splenocytes by preactivation with CD3 and were then cultured in the presence (CD3-AK [CD³⁺]) or absence (CD3-AK [CD3^-]) of CD3. The conventional lymphokine-activated killer (LAK) cells were induced by culturing DBA/2 splenocytes with purified human recombinant interleukin 2. Testing their in vitro cytotoxicity against syngeneic mastocytoma P815, CD3-AK (CD3⁺) cells gave the highest levels of cytotoxicity and were 20-fold higher than LAK cells and 200-fold higher than CD3-AK (CD3^-) cells. However, the cytotoxic activity of LAK or CD3-AK (CD3^-) cells was augmented by preincubating them with CD3 for 3 h; then, the difference in cytotoxic activity was reduced from 20- to 4-fold and from 200- to 2-fold, respectively. The in vivo antitumor activity of these killer cells paralleled the in vitro activity. In tests using tumor neutralization experiments, 80–100% of the mice that were challenged with 1 x 10² P815 cells remained tumor free after receiving 5 x 10⁶ CD3-AK (CD3⁺) cells. When the challenge dose increased to 1 x 10³ and to 1 x 10⁴ cells, giving CD3-AK (CD3⁺) cells slowed down the rate of tumor growth but only 20% of the mice remained tumor free. The untreated LAK cells or CD3-AK (CD3^-) cells did not induce any protection. After preincubation with CD3 for 3 h, the CD3-AK (CD3^-) cells provided protection in 30% of the challenged mice. The phenotype of effectors for mediating the in vitro and in vivo antitumor activities was found to be Thy1⁺, CD4^-, and CD8⁺ cells. Flow microfluorometry analysis showed that the higher levels of cytotoxic activity obtained with CD3-AK (CD3⁺) cells could not be simply explained by the increase of CD8⁺ cells, and the cytotoxic activity of individual CD3-AK (CD3⁺) cells appeared to be much higher than that of the LAK cells. After tumor growth was established for 1–2 days, giving CD3-AK (CD3⁺) cells slowed down the rate of tumor growth, and 20% of the mice remained tumor free. These results indicate that CD3-AK cells may be used in the immunotherapy of tumor growth. Major advantages of using CD3-AK cells are their high levels of antitumor activity and their fast growth in vitro; they can be expanded to a 10,000- to 100,000-fold increase in cell numbers in 2–3 weeks. Therefore, it appears that CD3-AK may be an ideal candidate for use in the adjuvant immunotherapy of tumor growth.

¹ To whom requests for reprints should be addressed, at Building 10, Room 4B17, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Received 12/12/88. Revised 3/31/89. Revised 5/10/89. Accepted 5/30/89.

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