Pilot Study of a Dual Gene Recombinant Avipox Vaccine Containing Both Carcinoembryonic Antigen (CEA) and B7.1 Transgenes in Patients with Recurrent CEA-expressing Adenocarcinoma

Autor: Reviewer: Ryan P. Smith, MD
Contribuidor de contenido: The Abramson Cancer Center of the University of Pennsylvania
Fecha de la última revisión: July 04, 2004

Authors: von Mehren M, et al.
Source:Clinical Cancer Research, 6, 2000, pg 2219

Background

  • The development of cancer vaccines has been attempted for over a century
  • Recent developments have given insight into the immune response, paving the way more avenues to exploit to make cancer vaccines more efficacious
  • A wealth of preclinical data indicate that tumor-specific antigens can mediate an effective antitumor response by the induction of cytotoxic T-cells
  • One such tumor antigen is CEA, found in 50% of breast cancers and in >90% of colorectal and gastric adenocarcinomas and in up to 80% of lung adenocarcinomas
  • Recently, it has also been discovered that a second signal, called a co-stimulatory molecule, is required for T-cell activation
  • Likely the most well-known co-stimulatory molecule is B7.1, which induces cytokines including IL-2 and IFN- g which in turn stimulate and amplify the immune response
  • ALVAC-CEA B7.1 is a viral vector (to deliver the tumor antigen (CEA) and the co-stimulatory molecule (B7.1) to cells) used in vaccines, as it is nonreplicating in humans but efficiently expresses the desired genes
  • This paper reports on a pilot study of 39 patients with advanced CEA-producing adenocarcinoma treated with the recombinant vaccine ALVAC-CEA B7.1

Materials and Methods

  • Patients with metastatic CEA-expressing adenocarcinoma who had failed standard therapy were eligible for the study
  • Patients were excluded if they had evidence of immunocompromise including any autoimmune disease, prior radiation of >50% of all nodal groups, prior splenectomy, or current use of steroids
  • As this was a phase I trial, there was an initial dose escalation phase using 2.5 x 10 7 plaque forming units of the viral vaccine (n=3), followed by escalation to 1.0 x 10 8 plaque forming units (n=6), followed by vaccination with the working dose of the vaccine, 4.5 x 10 8 plaque forming units (n=30)
  • The vaccine was given as an intradermal injection every two weeks for four injections. Patients with evidence of objective response or stable disease at eight weeks were allowed to continue on study, receiving boost injections every four weeks, with reevaluation every eight weeks
  • Patients were removed from the study upon disease progression
  • Patients receiving the dose of 4.5 x 10 8 plaque forming units had biopsies of the vaccine site 48 hours after injection to observe necrosis, dermal leukocytic infiltration, and inflammation
  • Patients' sera was tested for CEA antibodies using an ELISA
  • To assess for anti-CEA T-cells, ELISPOT assays were done

Results

  • 39 patients with metastatic CEA-producing adenocarcinoma were enrolled, the majority of which had colorectal cancer
  • All patients had received prior chemotherapy, with a median number of three prior regimens
  • Vaccination with the ALVAC-CEA B7.1 vaccine was well-tolerated. Three additional patients were added to the 1.0 x 10 8 dose level because of a grade 3 fever in a patient, which subsequently proved to be related to pneumonia
  • The most frequent toxicity was local erythema and induration at the vaccine site, followed by flu-like symptoms following vaccination
  • Other toxicities (GI side effects and elevations in liver enzymes) did occur, but they were mild and could have been attributed to the patients' cancers as well as the vaccine
  • Only those patients receiving four doses of the 4.5 x 10 8 vaccine (n=30) were evaluable for response. Eight of these patients had stable disease at re-evaluation. There were no partial or complete responses
  • All patients had leukocytic infiltrates and inflammation in the biopsy sites, though <10% showed evidence of necrosis
  • Six patients had declines in their CEA while receiving the vaccine course
  • Only two patients (out of 31 measured) showed the induction of anti-CEA antibodies
  • T-cell assays were available for 15 patients, and 12 of the 15 patients had at least a two-fold increase in T-cells specific to CEA peptide. Three patients showed at least a four-fold increase with one patient showing a nine-fold and another showing a 14-fold increase in CEA-specific T-cells
  • The only significant predictor of a T-cell response was the number of prior chemotherapy regimens

Authors' Conclusions

  • Vaccination with ALVAC-CEA B7.1 is safe for patients with metastatic CEA-expressing adenocarcinoma
  • The vaccine shows local immune reactivity and can induct CEA-specific T-cells
  • Twenty percent of all study participants and 27% of all evaluable patients had stabilization of disease after four injections

Scientific Implications

Insight into the role of co-stimulatory molecules provides an area that can be exploited to increase the efficacy of cancer vaccines. Challenges still remain related to the immune response. Namely, the correct tumor antigen is required, adequate delivery is needed, and care to avoid the induction of too brisk of an immune response (which could lead to autoimmunity) must be done. This study investigated the use of a vaccine consisting of a viral vector with CEA antigen and a co-stimulatory molecule. In terms of its phase I dose escalation aspect, the trial is a success, as the vaccine was very well-tolerated. However, the investigators went on to enroll a number of patients in the highest dose level in almost a phase II design in an attempt to prove efficacy. This was not as successful. Seldom were antibodies to CEA found, which may not predict the level of immune response anyway. Also, only 12 patients showed an increase in CEA-specific T-cells and only eight patients had stable disease. Though this does not rule out efficacy of the vaccine per se, it rather illustrates the fact that patient selection needs to be more specific. It is likely that only a subset of patients (perhaps with a specific HLA subtype) could inherently respond to the vaccine. Also, perhaps it would be much more efficacious in patients who were not already immunocompromised by multiple prior chemotherapy regimens (as evidenced by the chemotherapy regimens inversely predicting T-cell responses). Any vaccine as a single agent will fight an uphill battle to display efficacy before these obstacles are overcome.

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