Synchronized autologous T-cell immunotherapy with hyperthermia to previously heavy treated advanced renal cell carcinoma.

Purpose: Immune checkpoint inhibitors (ICIs) and target therapy have provided the clinical efficacy for improving the clinical progression-free survival (PFS) and overall survival (OS) for patients with renal cell carcinoma (RCC). There has been little report of an surrogate salvage treatment for those failure of both ICIs and target. An innovation therapeutic model named SHAPE-T (synchronized hyperthermia with autologous progenitor expanded T cells) was applied to previously heavily treated metastatic RCC (mRCC).

Vaccines targeting activating mutations elicit anti-tumor immune responses and suppress estrogen signaling in therapy resistant ER+ breast cancer.

ER+ breast cancers (BC) are characterized by the elevated expression and signaling of estrogen receptor alpha (, which renders them sensitive to anti-endocrine therapy. While these therapies are clinically effective, prolonged treatment inevitably results in therapeutic resistance, which can occur through the emergence of gain-of-function mutations in . The central importance of and development of mutated forms of suggest that vaccines targeting these proteins could potentially be effective in preventing or treating endocrine resistance.

Clinical trials of self-replicating RNA-based cancer vaccines.

Therapeutic cancer vaccines, designed to activate immune effectors against tumor antigens, utilize a number of different platforms for antigen delivery. Among these are messenger RNAs (mRNA), successfully deployed in some prophylactic SARS-CoV2 vaccines. To enhance the immunogenicity of mRNA-delivered epitopes, self-replicating RNAs (srRNA) that markedly increase epitope expression have been developed.

Combination of a novel heat shock protein 90-targeted photodynamic therapy with PD-1/PD-L1 blockade induces potent systemic antitumor efficacy and abscopal effect against breast cancers.

Background: We previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induction of systemic antitumor immunity by HS201-PDT alone or by the combination strategy with immune checkpoint blockade has yet to be determined.

Methods: Using unilateral and bilateral implantation models of syngeneic breast tumors (E0771, MM3MG-HER2, and JC-HER3) in mice, we assessed whether HS201-PDT could induce local and systemic antitumor immunity.

HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study.

A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of numerous oncogenic drivers, including the androgen receptor and its variants, to detect aggressive prostate cancer. We linked a near-infrared fluorescing molecule to an HSP90 binding drug and demonstrated that this probe (designated HS196) was highly sensitive and specific for detecting implanted prostate cancer cell lines with greater uptake by more aggressive subtypes.

Blood microbiota diversity determines response of advanced colorectal cancer to chemotherapy combined with adoptive T cell immunotherapy.

Human microbiota influence the response of malignancies to treatment with immune checkpoint blockade; however, their impact on other forms of immunotherapy is poorly understood. This study explored the effect of blood microbiota on clinical efficacy, represented by progression-free survival (PFS) and overall survival (OS), of combined chemotherapy and adoptive cellular therapy (ACT) in advanced colon cancer patients. Plasma was collected from colorectal cancer patients (CRC) treated with either chemotherapy alone (oxaliplatin and capecitabine) (XELOX CT alone group, n = 19), or ACT with a mixed dendritic cell/cytokine-induced killer cell product (DC-CIK) + XELOX (ICT group, n = 20).

Changes in Peripheral Blood Regulatory T Cells and IL-6 and IL-10 Levels Predict Response of Pediatric Medulloblastoma and Germ Cell Tumors With Residual or Disseminated Disease to Craniospinal Irradiation.

Purpose: Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described.

Methods And Materials: The study population consisted of children (n = 83, aged 3~18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors (GCT), and central nervous system embryonal tumor-not otherwise specified), with or without residual or disseminated (R/D) diseases who were starting standard postoperative focal or craniospinal irradiation (CSI).

Serial assessment of circulating T lymphocyte phenotype and receptor repertoire during treatment of non-muscle invasive bladder cancer with adoptive T cell immunotherapy.

Recurrence and progression of non-muscle-invasive bladder cancer (NMIBC), frequent despite the availability of multiple treatment modalities, may be partly explained by the presence of immunosuppressive cell populations. We hypothesized that progression of disease could be prevented by the administration of an activated T cell immunotherapy (ACT) at time points when immunosuppressive populations increased in peripheral blood. In an N-of-1 study, a patient with multiple primary bladder high grade urothelial carcinomas, previously treated with standard local resection and chemotherapy but with evidence of progression, received ACT consisting of dendritic cells mixed with cytokine induced killer cells (DC/CIK), intravenously 18 times over a 6 year period at indicated time of observed increases in peripheral blood immunosuppressive CD8/CD28 cells.

Infiltration of metastatic lymph nodes with PD-1 T cells is associated with improved disease-free and overall survival in resected N NSCLC.

Tumor metastases to regional lymph nodes are associated with worse outcome for patients with resected non-small cell lung cancer (NSCLC), but there is a wide variation in survival. We hypothesized that infiltration of tumor-involved lymph nodes with activated effector T cells would impact subsequent outcome. A total of 54 lymph nodes (27 N and 15 N collected from 12 patients with Stage IIB (TNM) and 12 N lymph nodes collected from 10 patients with Stage IIA (TNM) who underwent lymphadenectomy during surgical management of their NSCLC) were analyzed for effector T cells expressing activation markers PD-1 and TIM-3 using the -multiple immunofluorescence assay.

Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio.

Background: There remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.

Clinical efficacy of intra-cavitary infusions of autologous dendritic cell/cytokine-induced killer cell products for the treatment of refractory malignant pleural effusions and ascites.

To explore the safety and efficacy of intra-cavitary infusions of autologous mixed dendritic cell (DC)-cytokine-induced killer (CIK) cell products in advanced cancer patients with malignant pleural effusions or ascites. DC-CIKs were expanded ex vivo (mean yield of 1.36×10 cells (range, 0.

Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors.

To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors. Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT + ACT ( = 10), HT + ACT + anti-PD-1 inhibitor (pembrolizumab) ( = 11) and HT + ACT + CT ( = 12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment.

Predictive significance of T cell subset changes during generation of adoptive cellular therapy products for the treatment of advanced non-small cell lung cancer.

Adoptive T cell immunotherapy with cytokine-induced killer cells (CIKs) has been demonstrated to prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). The aim of the present study was to evaluate whether the expansion of effector T cells and the decrease of regulatory T cells (Tregs) that occurred during the generation of DC-CIKs were associated with improved clinical outcome in patients who received treatment. CIKs were generated over a 28-day period from the peripheral blood apheresis product of 163 patients with advanced cancer (including 30 with NSCLC).

Adoptive immunotherapy with autologous T-cell infusions reduces opioid requirements in advanced cancer patients.

Relief of cancer-related pain remains challenging despite the availability of a range of opioid and nonopioid medications. Animal models demonstrate that T lymphocytes may mediate analgesia by producing endogenous opioids, but definitive clinical data are limited. Transfer of ex vivo adoptive cellular therapy (ACT) is being tested as an anticancer therapy.

Impact of synchronized anti-PD-1 with Ad-CEA vaccination on inhibition of colon cancer growth.

The purpose of this study was to determine whether addition of anti-PD-1 antibody increased the immunogenicity and anti-tumor activity of Ad-CEA vaccination in a murine model of colon cancer. Ad-CEA was administered prior to implantation of MC-38-CEA cells followed by administration of anti-PD-1 antibody. CEA-specific T-cell responses were measured by flow cytometry and ELISPOT.

Functional CD3CD8PD1 T Cell Accumulation and PD-L1 Expression Increases During Tumor Invasion in DCIS of the Breast.

Background: The changes in T cell subsets and programmed death ligand 1 (PD-L1) expression during the transition from ductal carcinoma in situ (DCIS) to early invasive breast cancer had not been well studied.

Patients And Methods: A total of 85 DCIS patients were classified into 49 DCIS (clinical stage: Tis, noninvasive) and 36 with a minimally infiltrating lesion (MIL; < 5 mm; clinical stage: T1a). We explored the quantitative alterations of T-cell markers and PD-L1 in these groups using the Opal multi-immunohistochemistry technique.

Prospective randomized comparative study on rivaroxaban and LMWH for prophylaxis of post-apheresis thrombosis in adoptive T cell immunotherapy cancer patients.

Autologous adoptive T cell immunotherapy has been recognized as an effective treatment for cancer patients. The initial qualified lymphocytes is the core element determining the immunotherapeutic outcomes clinically. Cell separator based apheresis procedure is an optimal procedure to collect adequate mono-nucleated lymphocytes to generate efficient ex vivo T cell expansions; however, potential catheter-associated femoral vein thrombosis at post-apheresis might rise an additional deteriorated morbidity for cancer patients.

Vaccine-Induced Memory CD8 T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.

Purpose: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2).

Autologous Dendritic Cell-Cytokine Induced Killer Cell Immunotherapy Combined with S-1 Plus Cisplatin in Patients with Advanced Gastric Cancer: A Prospective Study.

Purpose: We have assessed the combination of DC-CIK with S-1 plus cisplatin chemotherapy in advanced gastric cancer (AGC) and the role of mutational analysis of circulating tumor DNA (ctDNA) and T-cell receptor (TCR) repertoire in predicting clinical outcomes.

Patients And Methods: Consecutive patients ( = 63) with AGC were allocated to treatment with S-1 alone, S-1 plus cisplatin, DC-CIK combined with S-1 or DC-CIK combined with S-1 plus cisplatin. The primary endpoints were progression-free survival (PFS) and overall survival (OS) at 1 year; the secondary endpoints were disease control rate and analysis of ctDNA and TCR repertoire.

Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers.

Background: Upregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine.

CYP1A1 genetic polymorphism is a promising predictor to improve chemotherapy effects in patients with metastatic breast cancer treated with docetaxel plus thiotepa vs. docetaxel plus capecitabine.

Purpose: A prospective study was performed to compare the outcome for metastatic breast cancer (MBC) patients treated with docetaxel plus thiotepa (DT) or docetaxel plus capecitabine (DC), and to explore the value of CYP1A1*2C polymorphisms in predicting clinical efficacy of these chemotherapies.

Methods: MBC patients (n = 130) were randomized to treatment with DT (n = 65) or DC (n = 65). Response rate, disease control rate, progression-free and overall survival were monitored.

Detection of HSP90 Identifies Breast Cancers with Aggressive Behavior.

Hsp90, a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers. We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive breast cancers. We exploited the uptake of an Hsp90 inhibitor by malignant cells to create an imaging probe (HS131) of Hsp90 activity by linking it to a near-infrared (nIR) dye.

Circulating CD8CD28 suppressor T cells tied to poorer prognosis among metastatic breast cancer patients receiving adoptive T-cell therapy: A cohort study.

Background Aims: This study aimed to determine the prognostic value of circulating CD8CD28 T lymphocytes among breast cancer patients treated with adoptive T-lymphocyte immunotherapy after chemotherapy.

Methods: Two hundred and thirty-two breast cancer patients underwent adoptive T-cell immunotherapy. Circulating CD8CD28 proportion was measured by flow cytometry.

Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition.

Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies.