Cellular and Humoral Immune Responses Induced by an HLA Class I–restricted Peptide Cancer Vaccine Targeting WT1 Are Associated With Favorable Clinical Outcomes in Advanced Ovarian Cancer

Despite the large number of potentially cytotoxic tumor-infiltrating (TIL) and tumor-associated (TAL) lymphocytes accumulated in the peritoneal cavity ascitic fluid and tumor tissue, advanced ovarian cancer is a progressive disease, suggesting that TIL and TAL populations eventually become functionally suppressed in vivo. Dendritic cells (DC) are the most powerful professional antigen presenting cells known in humans and recently, ovarian tumor antigen pulsed DC have been shown to elicit tumor specific human leukocyte antigens (HLA)-class I-restricted cytotoxicity from the peripheral blood of advanced ovarian cancer patients. In this study, we have evaluated the potential of tumor antigen-pulsed fully mature DC stimulation in restoring tumor-specific cytotoxicity in anergic TIL populations from advanced ovarian cancer patients. In addition, we have compared tumor-specific T-cell responses induced by tumor antigen-loaded DC in TIL to those induced in TAL and peripheral blood lymphocytes (PBL). DC stimulation induced powerful cytotoxicity against autologous tumor target cells in TIL-derived CD8+ T-cells from all patients tested, while autologous Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines (LCL) were not lysed. Killing of autologous tumor cells was higher by CD8+ T-cells from TIL compared to PBL and TAL (P < 0.01) and was more strongly inhibited by anti-HLA class I MAb (P < 0.05 compared to PBL and TAL). Phenotypically, all cytotoxic T lymphocyte (CTL) populations were CD3+/CD8+, with variable levels of CD56 expression. Finally, although a marked Type 1 cytokine bias [ie, interferon-gamma/interleukin-4 (IFN-γhigh/IL-4low)] was observable in all DC-stimulated CD8+ T-cell populations, TIL derived CD8+ T-cells showed a higher percentage of IFN-γ positive cells compared to TAL and PBL. Taken together, these data show that tumor lysate-pulsed DC can consistently restore strong CD8+ CTL responses from TIL against autologous ovarian cancer cells. DC-stimulated TIL may represent a superior source of tumor-specific CTL for adoptive T-cell immunotherapy for advanced ovarian cancer.

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Effect of the tumor-shed antigen CA125 on humoral immune responses of IgG1, IgG3, and IgM-type antibodies.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.15 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 15-15

Author(s):

J Bradford Kline

Keyword(s):

Ovarian Cancer ◽

Immune Responses ◽

Folate Receptor ◽

Standard Of Care ◽

Serum Levels ◽

Serum Samples ◽

Host Immune Responses ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Platinum Sensitive

15 Background: Human cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of CA125 on suppressing humoral immune responses of naturally occurring and therapeutic antibodies (Abs). These data stem from prespecified subgroup analysis of a Ph3 trial testing farletuzumab, a monoclonal Ab (mAb) to folate receptor alpha, plus standard-of-care carboplatin-taxane (CT) chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low CA125 serum levels treated with farletuzumab plus CT demonstrated improvements in PFS (HR 0.49, p = 0.0028) and OS (HR 0.44, p = 0.0108) compared to placebo plus CT. Farletuzumab utilizes Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with the aim to kill target bound tumor cells. These functions were analyzed in patient samples to determine if CA125 negatively impacts mAb-mediated humoral responses. Methods: Molecular and cell based assays tested the effects of CA125 on humoral immune activity mediated by mAbs on ovarian cancer patient serum samples. Results: Here we show that CA125 inhibits ADCC and CDC by directly binding to a subset of mAbs and perturbing engagement with Fc-γ activating receptors CD16a and CD32a and the C1q complement initiating protein. The effects occur via CA125 binding to the mAb variable domain, which alters the structure of the CH2 motif leading to suppressed binding by CD16a/CD32a and C1q. The lack of inhibition by the high affinity CD64a Fc-γ receptor as well as lack of FcRn inhibition suggests a conformational change occurs within the CH2 motif that perturbs the binding of low affinity CD16a, CD32a and C1q proteins. The effect appears to involve a subset of Abs composed of IgG1, IgG3 and IgM isotypes. Conclusions: CA125 has an immunosuppressive effect on Ab-mediated humor immunity in a subset of tested Abs of varied isotypes including IgG1, IgG3, and IgM. The effects have implications in monitoring therapeutic mAbs that may be negatively affected by CA125 binding as well as potential implications for identifying patients who may be at risk for developing certain types of cancer, including ovarian.

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The pH-Sensitive Fusogenic 3-Methyl-Glutarylated Hyperbranched Poly(Glycidol)-Conjugated Liposome Induces Antigen-Specific Cellular and Humoral Immunity

Clinical and Vaccine Immunology ◽

10.1128/cvi.00273-12 ◽

2012 ◽

Vol 19 (9) ◽

pp. 1492-1498 ◽

Cited By ~ 15

Author(s):

Takehisa Hebishima ◽

Eiji Yuba ◽

Kenji Kono ◽

Shin-nosuke Takeshima ◽

Yoshihiro Ito ◽

...

Keyword(s):

Immune Responses ◽

Mhc Class I ◽

Class I ◽

Delayed Type Hypersensitivity ◽

Murine Bone Marrow ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Hyperbranched Poly

ABSTRACTWe examined the ability of a novel liposome, surface modified by 3-methyl-glutarylated hyperbranched poly(glycidol) (MGlu-HPG), to enhance antigen-specific immunityin vitroandin vivoand to function as a vaccine carrier. Murine bone marrow-derived dendritic cells took up ovalbumin (OVA) encapsulated in MGlu-HPG-modified liposomes more effectively than free OVA or OVA encapsulated in unmodified liposomes. Immunization of mice with OVA-containing MGlu-HPG-modified liposomes induced antigen-specific splenocyte proliferation and production of gamma interferon (IFN-γ) more strongly than did immunization with free OVA or OVA encapsulated in unmodified liposomes. The immune responses induced by OVA encapsulated in MGlu-HPG-modified liposomes were significantly suppressed by addition of anti-major histocompatibility complex (MHC) class I and class II monoclonal antibodies, indicating the involvement of antigen presentation via MHC class I and II. Furthermore, delayed-type hypersensitivity responses and OVA-specific antibodies were induced more effectively in mice immunized with OVA encapsulated by MGlu-HPG-modified liposomes than with unencapsulated OVA or OVA encapsulated in unmodified liposomes. These results suggested that MGlu-HPG-modified liposomes effectively induced both cell-mediated and humoral immune responses. Collectively, this study is the first to demonstrate the induction of both cell-mediated and humoral immune responsesin vivoby MGlu-HPG-modified liposomes.

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