Cellular Immunotherapy: Using Alloreactivity to Induce Anti-Leukemic Responses without Prolonged Persistence of Donor Cells

Loren Fast,Peter Quesenberry,John Reagan

doi:10.3390/medsci1010037

Loren Fast, Peter Quesenberry + Show 1 more

Open Access

https://doi.org/10.3390/medsci1010037

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Journal: Medical Sciences	Publication Date: Nov 15, 2013
Citations: 56	License type: CC BY 4.0

Affiliation: Brown University, Rhode Island Hospital

Abstract

A goal of cancer immunologists is to harness cellular immune responses to achieve anti-cancer responses. One of the strongest activating stimuli for the immune system is the encounter with cells expressing allogeneic HLA molecules. While alloreactive responses can negatively impact of the outcome of hematopoietic stem cell transplant because of graft-versus-host disease (GVHD), these same responses can have anti-leukemic effects. Donor lymphocyte infusions have been used in an attempt to harness alloreactive responses to achieve anti-leukemic responses. Because this protocol is usually carried out in the absence of recipient anti-donor responses, this protocol often induces GVHD as well as anti-leukemic responses. A recent study indicated the infusion of large number of haploidentical donor cells (1–2 × 108 CD3+ cells/kg) into patients with refractory hematological malignancies (100 cGy total body irradiation) resulted in 14 (7 major) responses/26 patients. A rapidly developing cytokine storm was observed, while no persisting donor cells could be detected at two weeks after infusion eliminating the possibility of GVHD. Characterization of the effector mechanisms responsible for the anti-leukemic responses in this protocol, should guide new approaches for achieving enhanced anti-leukemic responses using this protocol.

Highlights

Alloreactivity is a property of the immune system in which a large fraction of T cells selected to recognize foreign peptides presented by self major histocompatibility complex (MHC) molecules are able to bind to allogeneic MHC molecules presenting endogenous peptides, often in a tissue dependent fashion [1]
Refractory leukemic patients will be infused with 1–2 × 108 CD3+ cells/kg obtained by pheresis from a haploidentical donor
The cellular immunotherapy protocol has been modified by collecting the white blood cells from the donor without prior G-CSF treatment and without the recipient receiving 100 cGy of total body irradiation prior to the infusion [59]

Summary

Introduction

Alloreactivity is a property of the immune system in which a large fraction of T cells selected to recognize foreign peptides presented by self major histocompatibility complex (MHC) molecules are able to bind to allogeneic MHC molecules presenting endogenous peptides, often in a tissue dependent fashion [1]. The lack of recipient immunity allows the donor alloreactive T cells present in the inoculum to initially engraft and later generate anti-recipient responses. Patients whose immune system had been significantly diminished by conditioning prior to a hematopoietic stem cell transplant and developed tolerance to the donor cells would not be expected to generate immune responses when mature donor lymphocytes were infused.

Results

Conclusion