Measurement of Quality of Life in Patients with Mycosis Fungoides/Sézary Syndrome Cutaneous T-Cell Lymphoma: Development of an Electronic Instrument.

BACKGROUND: Although the quality of life (QoL) plays an important role in treatment decision making and clinical management of mycosis fungoides (MF) or Sézary syndrome (SS) subtypes of cutaneous T-cell lymphomas (MF/SS-CTCLs), an MF- or SS-specific measure of QoL does not exist. OBJECTIVE: The objective of this research was to develop and validate the first QoL instrument for MF/SS-CTCL using a patient-centered approach. METHODS: A conceptual framework for the MF/SS-CTCL QoL was developed through a literature review and interviews with key opinion leaders. Concept elicitation with patients was utilized to refine the conceptual model and generate preliminary items. The items were then revised based on qualitative and quantitative feedback obtained through cognitive debriefing surveys and interviews with patients. Next, participants (N=126) completed the preliminary MF/SS-CTCL QoL and a comparator measure of health-related QoL (Skindex-29) through the PatientsLikeMe Open Research Exchange. The MF/SS-CTCL QoL was completed again 5 days later by 66 participants for the purposes of evaluating test-retest reliability. The MF/SS-CTCL QoL was finalized based on results from an empirical evaluation, which included both classical and modern test theory approaches. Specifically, this included evaluation of (1) the optimal item response theory measurement model; (2) item fit; (3) unidimensionality; (4) rating scale performance; (5) reliability; (6) test information (precision); (7) person-to-item map; (8) convergent and discriminant validity; and (9) presence of bias via differential item function. RESULTS: Results from the comprehensive psychometric evaluation utilizing a Rasch-Grouped Rating Scale model yielded a final 12-item instrument. The rating scale functioned as expected, and the instrument exhibited adequate person reliability (.87), good to excellent test-retest reliability (r=.89, P<.001), high levels of measurement precision, and good person-to-item targeting. The correlation between the MF/SS-CTCL QoL and the Skindex-29 (r=.852, P<.001) was significantly greater than the correlation between the MF/SS-CTCL QoL and syndrome stage (r=.260, P<.001), providing support for convergent and discriminant validity. Items did not show significant bias based on gender, age, or race. Rasch scores were converted to scaled scores with qualitative descriptive categories for ease of interpretation. CONCLUSIONS: Empirical evaluation demonstrated strong evidence of excellent psychometric properties. Utilizing a patient-centered measure development approach ensures that this QoL instrument captures the information that is most meaningful and clinically relevant to patients.

Chaperone-rich tumor cell lysate-mediated activation of antigen-presenting cells resists regulatory T cell suppression.

CD4(+)CD25(+) regulatory T lymphocytes (Tregs) critically contribute to the mechanisms of cancer-induced tolerance. These cells suppress anti-tumoral CD8(+) and CD4(+) T lymphocytes and can also restrain the function of APCs. We have previously documented the immunostimulatory effects of a chaperone-rich cell lysate (CRCL) anti-cancer vaccine. Tumor-derived CRCL induces tumor immunity in vivo, partly by promoting dendritic cell (DC) and macrophage activation. In the current study, we evaluated the effects of CD4(+)CD25(+)forkhead box P3(+) Tregs isolated from mice bearing 12B1 bcr-abl(+) leukemia on DC and macrophages that had been activated by 12B1-derived CRCL. CRCL-activated DC and macrophages resisted Treg suppression, as the production of proinflammatory cytokines, the activation of transcription factor NF-kappaB, and their immunostimulatory potential was unaffected by Tregs. Our results thus highlight CRCL as a powerful adjuvant endowed with the capacity to overcome tumor-induced Treg-inhibitory effects on APCs.

A chaperone protein-enriched tumor cell lysate vaccine generates protective humoral immunity in a mouse breast cancer model.

We have documented previously that a multiple chaperone protein vaccine termed chaperone-rich cell lysate (CRCL) promotes tumor-specific T-cell responses leading to cancer regression in several mouse tumor models. We report here that CRCL vaccine generated from a mouse breast cancer (TUBO, HER2/neu positive) is also capable of eliciting humoral immunity. Administration of TUBO CRCL triggered anti-HER2/neu antibody production and delayed the progression of established tumors. This antitumor activity can be transferred through the serum isolated from TUBO CRCL-immunized animals and involved both B cells and CD4(+) T lymphocytes. Further evaluation of the mechanisms underlying TUBO CRCL-mediated humoral immunity highlighted the role of antibody-dependent cell-mediated cytotoxicity. These results suggest that tumor-derived CRCL vaccine has a wider applicability as a cancer vaccine because it can target both T-cell- and B-cell-specific responses and may represent a promising approach for the immunotherapy of cancer.

Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10.

CD4(+)CD25(+) regulatory T cells have been characterized as a critical population of immunosuppressive cells. They play a crucial role in cancer progression by inhibiting the effector function of CD4(+) or CD8(+) T lymphocytes. However, whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear. To address this issue, we have evaluated the inhibitory potential of CD4(+)CD25(+) regulatory T cells from mice bearing a BCR-ABL(+) leukemia on bone marrow-derived dendritic cells. We present data demonstrating that CD4(+)CD25(+)FoxP3(+) regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-kappaB. The expression of the co-stimulatory molecules CD80, CD86 and CD40, the production of TNF-alpha, IL-12, and CCL5/RANTES by the suppressed DC is strongly down-regulated. The suppression mechanism requires TGF-beta and IL-10 and is associated with induction of the Smad signaling pathway and activation of the STAT3 transcription factor.

Natural killer cells play a key role in the antitumor immunity generated by chaperone-rich cell lysate vaccination.

Tumor derived chaperone-rich cell lysate (CRCL) when isolated from tumor tissues is a potent vaccine that contains at least 4 of the highly immunogenic heat shock proteins (HSP) such as HSP70, HSP90, glucose related protein 94 and calreticulin. We have previously documented that CRCL provides both a source of tumor antigens and danger signals triggering dendritic cell (DC) activation. Immunization with tumor derived CRCL elicits tumor-specific T cell responses leading to tumor regression. In the current study, we further dissect the mechanisms by which CRCL simulates the immune system, and demonstrate that natural killer (NK) cells are required for effective antitumor effects to take place. Our results illustrate that CRCL directly stimulates proinflammatory cytokine and chemokine production by NK cells, which may lead to activation and recruitment of macrophages at the tumor site. Thus, this report provides further insight into the function of CRCL as an immunostimulant against cancer.