Masayasu Naito

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

BACKGROUND Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. METHODS We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated. RESULTS At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. CONCLUSION Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT. TRIAL REGISTRATION Clinicaltrials.gov NCT00442130. FUNDING NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.

Identification of Lck-derived peptides applicable to anti-cancer vaccine for patients with human leukocyte antigen-A3 supertype alleles.

The identification of peptide vaccine candidates to date has been focused on human leukocyte antigen (HLA)-A2 and -A24 alleles. In this study, we attempted to identify cytotoxic T lymphocyte (CTL)-directed Lck-derived peptides applicable to HLA-A11+, -A31+, or -A33+ cancer patients, because these HLA-A alleles share binding motifs, designated HLA-A3 supertype alleles, and because the Lck is preferentially expressed in metastatic cancer. Twenty-one Lck-derived peptides were prepared based on the binding motif to the HLA-A3 supertype alleles. They were first screened for their recognisability by immunoglobulin G (IgG) in the plasma of prostate cancer patients, and the selected candidates were subsequently tested for their potential to induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A3 supertype+ cancer patients. As a result, four Lck peptides were frequently recognised by IgGs, and three of them – Lck90−99, Lck449−458, and Lck450−458 – efficiently induced peptide-specific and cancer-reactive CTLs. Their cytotoxicity towards cancer cells was mainly ascribed to HLA class I-restricted and peptide-specific CD8+ T cells. These results indicate that these three Lck peptides are applicable to HLA-A3 supertype+ cancer patients, especially those with metastasis. This information could facilitate the development of peptide-based anti-cancer vaccine for patients with alleles other than HLA-A2 and -A24.

Dexamethasone did not suppress immune boosting by personalized peptide vaccination for advanced prostate cancer patients.

To evaluate the immunological responses of personalized peptide vaccination combined with low‐dose glucocorticoids for advanced hormone refractory prostate cancer (HRPC) patients (pts).

Pilot study of the early start of chemotherapy after resection of primary colorectal cancer with distant metastases (Pearl Star 01)

BackgroundThe start of chemotherapy usually requires a delay of about 4 weeks after surgical resection of colorectal cancer. However, there is no evidence for the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. We therefore conducted a pilot study to determine the safety and feasibility of an early start of chemotherapy after the resection of colorectal cancer with distant metastases.MethodsFive patients were enrolled. They received XELOX therapy (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1 to 14) on the 7th postoperative day and XELOX + bevacizumab (7.5 mg/kg of bevacizumab on day 1) after the 2nd cycle of chemotherapy.ResultsFive patients underwent open surgery. The procedures included right hemicolectomy in 1 patient, sigmoidectomy in 2 patients, high anterior resection in 1 patient, and Hartmann procedure in 1 patient. All patients started chemotherapy on postoperative day 7. The median number of cycles of chemotherapy was 11 (8 to 22). No postoperative complications were observed. The tumor reduction rate was 44.3% (32.0 to 66.6%). Progression-free survival was 10.3 months.ConclusionsAn early start of chemotherapy after surgery is feasible and safe. These findings suggest possible changes in the start time of chemotherapy after surgery in the future. We have already started a new phase II trial to confirm the effects of the early start of chemotherapy after surgery.Trial registrationUMIN000004361.

A Report of Disseminated Carcinomatosis of the Bone Marrow Originating from Transverse Colon Cancer Successfully Treated with Chemotherapy Using XELOX plus Bevacizumab

A 61-year-old male, who had been admitted to another hospital due to disseminated intravascular coagulation (DIC), was referred to our hospital. Total colonoscopy, abdominal dynamic CT and positron-emission tomography revealed bone metastasis and multiple lymphocytic metastases from transverse colon cancer in addition to disseminated carcinomatosis of the bone marrow (DCBM). We immediately performed chemotherapy with XELOX + bevacizumab and denosumab against DCBM from transverse colon cancer in order to avoid radical surgery. In addition, we initiated the administration of recombinant human soluble thrombomodulin for 1 week to treat DIC. The patient was able to tolerate and receive 4 cycles of chemotherapy without any severe side effects. After receiving the 4 cycles of treatment, he recovered from DIC, and the bone and multiple lymphocytic metastases disappeared.

Multi-centric pancreatic cancer without PanIN lesion

The patient was a 67-year-old man under follow-up after gastric cancer surgery. An abdominal CT scan performed 1 year earlier had shown an approximately 14-mm hypovascular mass in the pancreatic body; however, he did not consent to treatment and was followed up for 1 year. A blood workup showed that the fasting blood glucose level, which had been within normal limits, was elevated to 174 mg/dl (normal, 70-109 mg/dl), and the HbA1c level was 12.0% (normal, 4.3-5.8%). Abdominal CT revealed an approximately 20-mm mass in the pancreatic body and an approximately 12-mm mass in the pancreatic tail, and magnetic resonance imaging cholangiopancreatography (MRCP) showed discontinuity of the main pancreatic duct (MPD). Since these findings led to the suspicion of invasive ductal carcinoma (IDC) of the pancreas developing in the pancreatic body and tail, we performed distal pancreatectomy with splenectomy. Histologically, IDCs were observed in the pancreatic body and tail. However, PanIN was not observed in the MPD between the two carcinomas. They were diagnosed as independent invasive ductal carcinomas of the pancreas.

A randomized phase II trial of personalized peptide vaccine with low dose cyclophosphamide in biliary tract cancer.

Since the prognosis of advanced biliary tract cancer (aBTC) still remains very poor, new therapeutic approaches, including immunotherapies, need to be developed. In the current study, we conducted an open‐label randomized phase II study to test whether low dose cyclophosphamide (CPA) could improve antigen‐specific immune responses and clinical efficacy of personalized peptide vaccination (PPV) in 49 previously treated aBTC patients. Patients with aBTC refractory to at least one regimen of chemotherapies were randomly assigned to receive PPV with low dose CPA (100 mg/day for 7 days before vaccination) (PPV/CPA, n = 24) or PPV alone (n = 25). A maximum of four HLA‐matched peptides were selected based on the pre‐existing peptide‐specific IgG responses, followed by subcutaneous administration. T cell responses to the vaccinated peptides in the PPV/CPA arm tended to be greater than those in the PPV alone arm. The PPV/CPA arm showed significantly better progression‐free survival (median time: 6.1 vs 2.9 months; hazard ratio (HR): 0.427; P = 0.008) and overall survival (median time: 12.1 vs 5.9 months; HR: 0.376; P = 0.004), compared to the PPV alone arm. The PPV alone arm, but not the PPV/CPA arm, showed significant increase in plasma IL‐6 after vaccinations, which might be associated with inhibition of antigen‐specific T cell responses. These results suggested that combined treatment with low dose CPA could provide clinical benefits in aBTC patients under PPV, possibly through prevention of IL‐6‐mediated immune suppression. Further clinical studies would be recommended to clarify the clinical efficacy of PPV/CPA in aBTC patients.

Endoscopic mucosal incision for successful treatment of submucosal abscess extending the full length of the esophagus due to fish bone: report of a case

Submucosal abscess of the esophagus is extremely rare, and treatment has yet to be well established. A 58-year-old man with no relevant past medical history visited an otolaryngological clinic with a chief complaint of throat irritation. Computed tomography revealed submucosal abscess extending the full length of the esophagus after abnormally high white blood cell count and C-reactive protein levels were noted. A fish bone was removed surgically via the right side of the neck, and the submucosal abscess was drained by endoscopic mucosal incision. Oral intake was started on postoperative day 10 and the patient was discharged without any complications. Endoscopic submucosal incision is a useful and less-invasive therapy for treating esophageal submucosal abscess.

Efficacy of XELOX plus Bevacizumab in Brain Metastasis from Rectal Cancer

Brain metastasis (BM) is rare in colorectal cancer (CRC) patients. Although BM from CRC is a late-stage phenomenon with an extremely poor prognosis, some subsets of patients would benefit from a multidisciplinary management strategy. The prognosis of patients with BM from CRC was associated with the curability of the therapy for BM and the number of metastatic organs. Metastatic brain tumors are generally treated with radiotherapy because many anticancer drugs cannot cross the blood-brain barrier. Here, we present a case treated with XELOX (capecitabine and oxaliplatin) plus bevacizumab for BM from rectal cancer. To our knowledge, this is the first report of a patient who was successfully treated for BM from CRC without radiotherapy. The findings could lead to a paradigm shift in the use of chemotherapy for BM from CRC.

Personalized Kampo Medicine Facilitated Both Cytotoxic T Lymphocyte Response and Clinical Benefits Induced by Personalized Peptide Vaccination for Advanced Esophageal Cancer

We retrospectively evaluated if personalized Kampo medicine (PKM) could facilitate CTL responses and clinical benefits induced by personalized peptide vaccination (PPV), in which HLA-matched vaccines were selected and administered based on the preexisting host immunity, for advanced esophageal cancer (aEC) patients. Among 34 aEC patients entered in the clinical study, 23 patients received PKM and PPV without (n = 12) or with chemotherapy (n = 11), while the remaining 11 patients did not receive PKM but received PPV without (n = 6) or with chemotherapy (n = 5), respectively. Incidence of adverse events was significantly lower or higher in PKM and PPV arm (n = 23) or PPV and chemotherapy arm (n = 16) as compared to that of the counter arm (n = 11 or 18), respectively. Postvaccination PBMCs from the patients undergoing PKM and PPV showed significantly higher CTL responses as compared to the counter arm. The median progression-free survival (PFS) or median survival time (MST) of 34 patients was 2.9 or 7.6 months, respectively. The combination therapy in PPV and PKM arm, but not that in PPV and chemotherapy arm, significantly (P = 0.02) prolonged MST. These results could warrant a next step of prospective clinical study of PKM and PPV for aEC patients.