Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

340 16 Immunocytokines: Versatile Molecules for Biotherapy of Malignant Disease
16.6.4
Amplification of Suboptimal CD8 + T Memory Cells by a Cellular Vaccine
Based on the superior efficacy of tumor targeted IL-2 as outlined in this chapter and
its role as an effective adjuvant for cancer vaccines emerging from clinical trials, we
hypothesized that tumor-specific targeting of IL-2 into the tumor microenvironment
is more effective in amplifying a cancer vaccine-induced T cell-mediated immune responses
than systemic IL-2.
This hypothesis was tested in two independent experimental systems with a cellular
vaccine consisting of NXS2 neuroblastoma cells genetically engineered to produce
single-chain IL-12 [104] and, as described above, in the CT26-KSA colon carcinoma
model, following induction of a vaccination effect by targeted IL-2 using huKS1/4±
IL-2 fusion protein. We could demonstrate in both systems that the initial T cell response
is effectively amplified by tumor-specific targeting of IL-2 into the tumor microenvironment
with tumor-specific immunocytokines ch14.18±IL-2 [105] and
huKS1/4±IL-2 [15], respectively. This was clearly indicated in the NSX2 neuroblastoma
model by the complete absence of metastases in the majority of animals that
were challenged by lethal i.v. injection with wild-type tumor cells up to 90 days after
the initial vaccination and followed by injections with non-curative doses of tumorspecific
immunocytokines. However, administration of non-specific immunocytokines
or equivalent mixtures of tumor-specific antibody and IL-2 were completely ineffective
[15, 105]. This is illustrated by the data shown in Tab. 16.4. In this case, A/J
mice were vaccinated by s.c. injection of 5 × 10 6 NXS2 cells genetically engineered to
produce scIL-12 and challenged by a lethal i.v. injection of 5 × 10 4 NXS2 wild-type
cells 90 days after initial vaccination. Treatment was initiated at day 5 after tumor
cell challenge by 5 daily i.v. injections of PBS; 10 mg of ch14.18 antibody plus 30 000
units of rhIL-2, 10 mg of the non-specific ch225±IL-2 fusion protein or 10 mg of the
tumor-specific ch14.18±IL-2 fusion protein. Liver metastases were staged according
to the percentage of metastatic liver surface as follows: 0, 0%; 1, 75%. Data for liver weight were the mean +SD. Differences in bone
marrow staging, liver metastasis and liver weights between fusion-protein-treated
mice and all control groups were statistically significant (P < 0.01).
Increases in CD25 + /CD8 + Tcells, MHC class I-restricted target cell killing, and Vb11
and Vb13 T cell receptor usage suggested a mechanism for reactivation of CD8 +
memory T cells induced by the vaccine effectively boosted with ch14.18±IL-2 [105].
Tab. 16.4 Boost of gene therapy-induced immunoprotection with recombinant ch14.18±IL-2
fusion protein
Vaccine Treatment Metastatic score Liver weight (mg)
scIL 12 NXS2 PBS 4,4,3,2,1,1 2011+986
scIL 12 NXS2 ch14.18 + IL-2 3,2,2,1 1530+320
scIL 12 NXS2 ch225±IL-2 4,3,2,2,1,1 1610+357
scIL 12 NXS2 ch14.18±IL-2 0,0,0,0,0,0 912+126