Multivirus-specific Cytotoxic T Lymphocytes (mCTL)

Since recovery of virus-specific T cells is clearly associated with protection from infection with each of these viruses, adoptive immunotherapy to decrease the time to immune reconstitution is an attractive approach. Virus-specific T cells generated by repeated stimulation with antigen presenting cells (APCs) expressing viral antigens have been evaluated in clinical trials to prevent and treat viral infections in immunocompromised hosts. This approach eliminates alloreactive T cells.

To broaden the specificity of single CTL lines to include the three most common viral pathogens of stem cell recipients, investigators reactivated CMV and adenovirus-specific T cells by using mononuclear cells transduced with a recombinant adenoviral vector encoding the CMV antigen pp65 (Ad5f35CMVpp65). Subsequent stimulations with EBV-LCL transduced with the same vector both reactivated EBV-specific T cells and maintained the expansion of the activated adenovirus and CMV-specific T cells. This method reliably produced CTLs with cytotoxic function specific for all three viruses, which investigators infused into 14 stem cell recipients in a Phase I prophylaxis study. They observed recovery of immunity to CMV and EBV in all patients but an increase in adenovirus-specific T cells was only seen in patients who had evidence of adenovirus infection pre-infusion. A follow-up study in which the frequency of adenovirus-specific T cells was increased in the infused CTLs produced similar results, thus highlighting the importance of endogenous antigen to promote the expansion of infused T cells in vivo. Nevertheless, all patients in both clinical trials with pre-infusion CMV, adenovirus or EBV infection or reactivation were able to clear the infection, including one patient with severe adenoviral pneumonia requiring ventilatory support. CTLs recognizing multiple antigens can therefore produce clinically relevant effects against all three viruses.

Inclusion criteria

• Diagnosis of primary immunodeficiency with established plan to undergo myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant for treatment thereof or diagnosis of a form of primary immunodeficiency for which hematopoietic stem cell transplantation is not indicated.
• Active infection with EBV, CMV, and/or Adenovirus, unable to be successfully controlled with standard therapy.
• Steroids less than 0.5 mg/kg/day prednisone
• Karnofsky/Lansky score of ≥ 50
• ANC greater than 500/µL.
• Bilirubin <2x, AST <3x, Serum creatinine <2x upper limit of normal, Hgb >8.0
• Pulse oximetry of > 90% on room air
• Negative pregnancy test (if female of childbearing potential)
• Patient or parent/guardian capable of providing informed consent.

Exclusion criteria

• Patients with other uncontrolled infections (see 2.3.2 for definitions)
• Patients who received ATG, Campath, or other T cell immunosuppressive monoclonal antibodies in the last 28 days
• Received donor lymphocyte infusion in last 28 days
• Diagnosis of Omenn's syndrome or MHC class I deficiency
• Active and uncontrolled malignancy
• Pregnant or lactating
• Unable to wean steroids to ≤0.5 mg/kg/day prednisone.
• Patients with Grade 3 hyperbilirubinemia