Asunto(s)
Quimioradioterapia/efectos adversos , Erupciones por Medicamentos/epidemiología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/terapia , Radiodermatitis/epidemiología , Quimioradioterapia/métodos , Ensayos Clínicos como Asunto , Erupciones por Medicamentos/inmunología , Humanos , Incidencia , Neoplasias/inmunología , Radiodermatitis/inmunologíaRESUMEN
We conducted a phase I trial of allogeneic T cells sensitized in vitro against a pool of pentadecapeptides (15-mer peptides) spanning the sequence of CMVpp65 for adoptive therapy of 17 allogeneic hematopoietic cell transplant recipients with cytomegalovirus (CMV) viremia or clinical infection persisting despite prolonged treatment with antiviral drugs. All but 3 of the patients had received T cell-depleted transplants without graft-versus-host disease (GVHD) prophylaxis with immunosuppressive drugs after transplantation. The CMVpp65-specific T cells (CMVpp65CTLs) generated were oligoclonal and specific for only 1 to 3 epitopes, presented by a limited set of HLA class I or II alleles. T cell infusions were well tolerated without toxicity or GVHD. Of 17 patients treated with transplant donor (n = 16) or third-party (n = 1) CMVpp65CTLs, 15 cleared viremia, including 3 of 5 with overt disease. In responding patients, the CMVpp65CTLs infused consistently proliferated and could be detected by T cell receptor Vß usage in CMVpp65/HLA tetramer + populations for period of 120 days to up to 2 years after infusion. Thus, CMVpp65CTLs generated in response to synthetic 15-mer peptides of CMVpp65 are safe and can clear persistent CMV infections in the post-transplantation period.
Asunto(s)
Infecciones por Citomegalovirus , Citomegalovirus/inmunología , Trasplante de Células Madre Hematopoyéticas , Transfusión de Linfocitos , Péptidos/inmunología , Fosfoproteínas/inmunología , Linfocitos T , Donantes de Tejidos , Proteínas de la Matriz Viral/inmunología , Viremia , Anciano , Aloinjertos , Niño , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/patología , Infecciones por Citomegalovirus/terapia , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Péptidos/farmacología , Fosfoproteínas/farmacología , Linfocitos T/inmunología , Linfocitos T/patología , Linfocitos T/trasplante , Proteínas de la Matriz Viral/farmacología , Viremia/inmunología , Viremia/patología , Viremia/terapiaRESUMEN
Delayed T cell recovery and restricted T cell receptor (TCR) diversity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and cancer relapse. Technical challenges have limited faithful measurement of TCR diversity after allo-HSCT. Here we combined 5' rapid amplification of complementary DNA ends PCR with deep sequencing to quantify TCR diversity in 28 recipients of allo-HSCT using a single oligonucleotide pair. Analysis of duplicate blood samples confirmed that we accurately determined the frequency of individual TCRs. After 6 months, cord blood-graft recipients approximated the TCR diversity of healthy individuals, whereas recipients of T cell-depleted peripheral-blood stem cell grafts had 28-fold and 14-fold lower CD4(+) and CD8(+) T cell diversities, respectively. After 12 months, these deficiencies had improved for the CD4(+) but not the CD8(+) T cell compartment. Overall, this method provides unprecedented views of T cell repertoire recovery after allo-HSCT and may identify patients at high risk of infection or relapse.