Immune-maximizing (IMAX) therapy for cancer: Combination of dendritic cell vaccine and intensity-modulated radiation.

A dendritic cell (DC)-based vaccine was combined with intensity-modulated radiotherapy (IMRT) or other conformal radiotherapy (RT), assuming minimal immunosuppression by such RT modalities. In this study, the outcomes in the first 40 patients are presented. The patients had recurrent, metastatic or locally advanced tumors. Nine had previously undergone full-course RT. Peripheral blood mononuclear cells obtained by leukapheresis were cultured with granulocyte-macrophage colony-stimulating factor, interleukin-4, OK-432 and prostaglandin E2 to generate DCs, which were pulsed with autologous tumor lysates or tumor-specific peptides, such as WT1. IMRT using tomotherapy, stereotactic irradiation or 3-dimensional conformal RT (3DCRT) was initially administered. The standard dose was 30 and 60 Gy in patients with and without previous RT, respectively. Every other week thereafter, up to a total of 7 times, DC vaccines were injected directly into the tumor (n=15) or administered intradermally when DCs were pulsed with tumor lysates or peptides. The tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST). RT and DC vaccines were well tolerated and there were no major complications. Three patients were not able to complete the planned DC therapy due to disease progression. For the 31 patients receiving full-dose RT, the response rate was 61% and for the 9 patients who had previously received RT, the response rate was 55%. In 9 patients, the tumor response outside the RT target volume was evaluable: 22% had a partial response (PR), 33% had stable disease (SD) and 44% had progressive disease (PD). In conclusion, a combination of IMRT (or 3DCRT) and DC vaccine is feasible and requires further investigation.

HLA class I and II gene polymorphisms in Stevens-Johnson syndrome with ocular complications in Japanese.

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents and/or inciting drugs. Although the pathobiological mechanisms underlying the onset of SJS/TEN have not been fully established, the extreme rarity of cutaneous and ocular surface reactions to drug therapies led us to suspect individual susceptibility. Our previous study of polymorphisms in the HLA-class I genes of 40 Japanese SJS/TEN patients with ocular surface complications showed that in the Japanese, HLA-A*0206 was strongly associated with SJS/TEN. In this study, we investigated the association between HLA class II antigens in addition to HLA class I antigens and SJS/TEN. METHODS: We studied the histocompatibility antigen genes, HLA-A, B, C, DRB1, and DQB1, of 71 Japanese SJS/TEN patients with ocular complications. We also genotyped 113 healthy volunteers for HLA-A, B, C, DRB1, and DQB1. We performed polymerase chain reaction amplification followed by hybridization with sequence-specific oligonucleotide probes (PCR-SSO) using commercial bead-based typing kits. RESULTS: HLA-A*0206 was strongly associated with SJS/TEN. HLA-A*1101 was inversely associated. HLA-B*5901 exhibited a high odds ratio for SJS/TEN with ocular complications. However, when we corrected the p-value for the number of alleles detected (n=29), the results ceased to be significant. There was no association between HLA-C and SJS/TEN. There was also no significant association between HLA-DRB1 and SJS/TEN. HLA-DQB1*0502 was negatively and weakly associated with SJS/TEN although correction of the p-value for the number of alleles detected rendered the result not significant. CONCLUSIONS: Because our findings are completely different from data reported on Caucasian patients, they suggest strong ethnic differences in the HLA-SJS associations.

Phlyctenular keratitis associated with meibomitis in young patients.

PURPOSE: To describe the unique clinical features of phlyctenular keratitis, including the association with meibomitis, in young patients. DESIGN: Observational case series. METHODS: The study population consisted of 23 Japanese patients aged under 35 years with phlyctenular keratitis. We examined their clinical history, signs and symptoms, human leukocyte antigen (HLA), bacterial cultures of meibum, and the efficacy of antibiotics. The minimal diagnostic criteria included corneal nodules consisting of cellular infiltrates and superficial neovascularization. RESULTS: Of the 23 patients, 20 (87%) were women, and 13 (56.5%) had a history of chalazia. In all cases, the lesions and the severity of corneal nodules and neovascularization corresponded well with the location and the severity of meibomitis. The frequency of HLA-A26 and HLA-B35 was significantly increased in our patients (P = .003 and .016, respectively). Propionibacterium acnes in bacterial cultures of pure meibum in 12 of the 20 patients (60%) was statistically more highly positive than those in four of the 17 age-matched normal control subjects (23.5%; P = .028). CONCLUSION: The characteristics of phlyctenular keratitis in our cases include significantly higher prevalence in female patients, severity variation of ocular surface manifestation corresponding to meibomitis, specific HLA association, and possible P. acnes involvement.

[A case of unresectable multiple liver metastases from colon cancer successfully treated by hepatic arterial infusion chemotherapy and systemic immunotherapy (IFNANK) followed by hepatic resection].

The patient was a 76-year-old man, diagnosed with sigmoid colon cancer with unresectable multible liver metastases. After sigmoidectomy with D2 regional lymphnode dissection on June 21, 2002 (moderately differentiated adenocarcinoma, ss, n(-), H3, P0, M(-), Stage IV), intermittent hepatic arterial infusion chemotherapy using 5-FU (1,250 mg/body/3 hr) and CDDP (10 mg/body/30 min) was performed weekly for 23 times, and then biweekly for 15 times. The total dosages of 5-FU were 47.5 g. During the regional chemotherapy, IFNANK therapy was performed biweekly as systemic immunotherapy. As a result, serum levels of tumor markers were remarkably decreased, and the metastatic liver tumors had disappeared in the CT finding in July 2003. Thereafter, IFNANK therapy was continued without the chemotherapy. However, CT and PET detected the recurrent liver tumors in December 2003, and the tumors were curatively resected on January 28, 2004.

Liposomal lactoferrin induced significant increase of the interferon-alpha (IFN-alpha) producibility in healthy volunteers.

Interferon-alpha (IFN-alpha) producibility has been widely accepted as one of the important markers to evaluate the immune status. In this study, preliminary clinical tests were carried out to confirm the immunomodulatory activity of liposomal lactoferrin including IFN-alpha producibility and NK activity. In a primary open trial, the liposomal lactoferrin was administered to five healthy males for one week and various immunological indices were evaluated. Furthermore, ten healthy males were administered 319 mg per day of liposomal or non-liposomal lactoferrin for four weeks, and immune status was monitored at 0, 1 and 4 weeks after the intake as well as three weeks after stopping it. In this double-blinded comparative study, the IFN-alpha producibility was significantly increased only in the liposomal lactoferrin group during administration and decreased 3 weeks after stopping it, while the IFN-alpha producibility was unchanged in the non-liposomal lactoferrin group. Although the biological mechanism of IFN-alpha producibility enforced by liposomal lactoferrin has not been wholly understood, it is suggested to be a novel active constituent having preventive and therapeutic effects on inflammatory diseases, cancer and infectious diseases such as chronic hepatitis C.

A series of immune responses leading to the induction of T cell IL-12/IL-18 responsiveness in patients with relatively large tumor burdens.

The induction of interleukin-12 (IL-12) responsiveness in T cells depends on T cell receptor (TCR) triggering, and is regarded as a parameter of recently TCR-sensitized T cells. Here, we investigated whether IL-12 responsiveness could be detected in freshly prepared T cells from tumor-bearing patients, and if so whether such patients exhibited additional immunological parameters related to IL-12 responsiveness. CD4(+) and CD8(+) T cell populations from an appreciable proportion of tumor-bearing patients exhibited high levels of IL-12 responsiveness as evaluated by IL-12-stimulated interferon-gamma (IFN-gamma) production. T cell populations with high IL-12 responsiveness were observed in the group of patients with moderate to large tumor mass or tumor metastases rather than in patients with small tumors. The frequency of such a T cell population was also lower in post-surgery tumor-free patients, showing the correlation between IL-12 responsiveness and the presence of a certain extent of tumor burden. More importantly, a higher incidence of IL-12 responsiveness was observed in tumor-bearing patients exhibiting detectable plasma IL-12 levels, and correlated with IL-18 responsiveness. T cell IL-12 and IL-18 responsiveness is induced by TCR triggering and subsequent IL-12 stimulation respectively. Furthermore, TCR-triggered T cells stimulate antigen-presenting cells (APC) to produce IL-12. Therefore, the present observations suggest that an immune response loop from TCR sensitization to the induction of IL-12/IL-18 responsiveness via IL-12 production operates in tumor-bearing patients, particularly in those with relatively large tumor burdens.

The association of HLA with young-onset keratoconus in Japan.

PURPOSE: To report the association of HLA antigens with keratoconus in Japanese patients. DESIGN: Observational consecutive case series. METHODS: In 90 consecutive Japanese keratoconus patients, HLA class I (HLA-A, -B, -C) and class II (HLA-DR, -DQ) were analyzed. RESULTS: Compared with control frequencies, based on mean gene frequencies for the Japanese population, higher frequencies of HLA-A26, B40, and DR9 antigens were found in patients whose conditions were diagnosed before 20 years of age (chi(2) = 6.45, P =.01; chi(2) = 6.78, P =.01; chi(2) =3.99, P =.05, respectively), but were not found in patients whose conditions were diagnosed later in life. Men were significantly younger at diagnosis than were women. No obvious relation was found between HLA antigens and other clinical data. CONCLUSION: HLA-A26, B40, and DR9, which were found relatively frequently in the ancient Japanese population, seem to be associated with keratoconus in younger individuals.