Multivirus-specific Cytotoxic T Lymphocytes (mCTL)
Condition: Refractory Viral Infections
MeSH terms: Infections; Virus Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      PIDD represent an expanding group of genetic disorders that compromise immunity against
      bacteria, viruses, and fungi. The most severe forms of PIDD cause profound susceptibility to
      opportunistic infections due to impaired or absent T-cell immunity. These diseases can be
      rapidly fatal unless treated via hematopoietic stem cell transplantation (HSCT). Chronic
      viral illnesses are a common presenting feature of many of these disorders, and studies have
      shown that survival of HSCT is profoundly impacted by the patient's pre-transplant disease
      status. Primary infections with viruses such as cytomegalovirus (CMV) and Epstein-Barr virus
      (EBV) are common, and respiratory viruses such as adenovirus also frequently cause infection.
      In patients with severe combined immunodeficiency (SCID), a prior study identified these
      viruses as the most common causes of mortality in the immediate period following HSCT. Though
      some forms of PIDD are amenable to HSCT without requiring conditioning chemotherapy, many
      forms require a variable degree of pre-conditioning to ensure that stable engraftment of the
      donor cells is achieved. The administration of cytotoxic chemotherapy used in the
      conditioning regimens can however increase the risk for regimen related toxicity and for some
      patients (especially those with active viral infections) this risk is particularly high,
      leading to high treatment related mortality rates. For these reasons, many such patients are
      not even considered candidates for HSCT or are delayed getting to HSCT and ultimately succumb
      to infection before they can receive the transplant.

      The primary objective of this study is to determine the safety of administering third-party
      multivirus-specific cytotoxic T lymphocytes (mCTL) from adult CMV seropositive donors to
      treat refractory viral infections in patients with primary immunodeficiency disorders (PIDD)
      prior to hematopoietic stem cell transplantation (HSCT).
    

Detailed description: 
      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.
    

Intervention name(s): mCTLs
Intervention type(s): Biological
Intervention description(s): The investigators have elected to limit this phase I study to PIDD patients with active viral infections unable to be controlled with standard pharmacotherapy, who are therefore likely to benefit from mCTLs treatment. This trial will be performed as dose-escalation study. Patients will be evaluated for matched lines from a bank of third-party mCTLs, derived from CMV seropositive donors. These lines will have been used clinically in prior clinical trials, with safety demonstrated in the post-HSCT setting.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment