Cell Therapy With Preimmunized Effector Cells Mismatched for Minor Histocompatible Antigens in the Treatment of a Murine Mammary Carcinoma

Abstract

Cell therapy with allogeneic donor cells mismatched for minor histocompatible (MiHC) antigens was applied to a murine mammary carcinoma (4T1) model to test the feasibility of graft versus tumor (GVT) effect against metastatic epithelial tumor cells. BALB/c mice bearing a 4T1 tumor of BALB/c origin were given syngeneic or MiHC-mismatched splenocytes. GVT effects were determined in secondary recipients of adoptively transferred lung cells derived from primary hosts who had previously been inoculated intravenously with 4T1 cells, and injected with one of the following: 1) naive BALB/c splenocytes, 2) naive DBA/2 splenocytes, 3) 4T1-immune DBA/2 splenocytes, or 4) DBA/2 splenocytes immunized with host-derived BABL/c spleen cells. Naive DBA/2 splenocytes inhibited tumor growth only slightly and only slightly prolonged the survival of secondary recipients, in comparison with fully matched tumor/host BALB/c spleen cells. An efficient GVT reaction was demonstrated in vitro and in vivo with MiHC-mismatched DBA/2 splenocytes from mice presensitized by multiple injections of irradiated tumor or BALB/c-derived spleen cells. All 30 mice adoptively inoculated with lung cells from primary hosts that had previously been treated with these presensitized effector cells were tumor free for >250 days. Secondary recipients inoculated with lung cells from mice given naive BALB/c or DBA/2 spleen cells died of metastatic tumors within 33 to 46 days. These results suggest that preimmunized donor cells represent an effective tool against metastatic disease; hence, the next goal should be to control graft-versus-host disease while exploiting the GVT potential.

Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic bone marrow chimeras

“…By day 13, the disease cannot be cured by surgery, chemotherapy, or lethal TBI followed by alloSCT. Consistent with previous observations, we found that allogeneic T cells could retard the development and/or growth of systemic metastases 10,11 (supplemental Figure S1a on the Blood website; see the Supplemental Figure link at the top of the online article), but only if the T cells had been taken from donors previously primed with cells that are syngeneic to the tumor. However, primed cells caused significant GVHD when administered shortly after lethal conditioning and alloSCT, 12,13 and they ultimately failed to control the growth of the primary tumor.…”

Allogeneic hematopoietic cell transplantation for metastatic breast cancer

“…33 This direct GVT effect mediated by the alloreactive donor splenocytes in the absence of any anti-carcinoma agents has also been demonstrated by direct inhibition of liver metastases through intraportal inoculation of allogeneic splenocytes but not syngeneic splenocytes. 34 Activated allogeneic natural killer splenocytes and allogeneic donor-specific CD8 þ cytotoxic T cells with a type 2 cytokine phenotype have also been shown induce a GVT Table 4 Bivariate analyses of conditioning and GVHD a on treatment-related mortality, disease relapse or progression and progression-free survival after allogeneic HCT for metastatic breast cancer…”

Allogeneic cell-mediated immunotherapy of leukemia with immune donor lymphocytes to upregulate antitumor effects and downregulate antihost responses

“…Regardless of the mechanism, the feasibility of inducing curative GVL effects by donor lymphocytes with no clinical evidence of GVHD was previously reported in BCL1-leukemia 4,5 as well as in other murine tumor models 6 and in man. 25,26 The observation that BCL1-immune cells were more effective than BALB-immune donor cells against BCL1 is not surprising. However, the finding that these cells can immunize the donor against tumor cells of host origin while responding minimally to host alloantigens should be further investigated.…”