Pathologic response assessment of tumor specimens from patients receiving systemic treatment provides an early indication of therapeutic efficacy and predicts long-term survival. Grading systems for ...pathologic response were first developed for chemotherapy in select tumor types. Immunotherapeutic agents have a mechanism of action distinct from chemotherapy and are being used across a broad array of tumor types. A standardized, universal scoring system for pathologic response that encompasses features characteristic for immunotherapy and spans tumor types is needed.
Hematoxylin and eosin-stained slides from neoadjuvant surgical resections and on-treatment biopsies were assessed for features of immune-related pathologic response (irPR). A total of 258 specimens from patients with 11 tumor types as part of ongoing clinical trials for anti-PD-(L)1 were evaluated. An additional 98 specimens from patients receiving anti-PD-(L)1 in combination with other treatments were also reviewed, including those from three additional tumor types.
Common irPR features (immune activation, cell death, tissue repair, and regression bed) were present in all tumor types reviewed, including melanoma, non-small cell lung, head and neck squamous cell, Merkel cell, and renal cell carcinoma, among others. Features were consistent across primary tumors, lymph nodes, and distant metastases. Specimens from patients treated with anti-PD-(L)1 in combination with another agent also exhibited irPR features.
irPR features are consistent across tumor types and treatment settings. Standardized, pan-tumor irPR criteria (irPRC) are defined and associated specimen-handling considerations are described. Future, prospective studies are merited to validate irPRC in larger datasets and to associate pathologic features with long-term patient outcomes.
In this report, we evaluated the efficiency of stable gene transfer into established CD8(+) human tumor antigen-specific cytotoxic T cell (CTL) lines and peripheral blood lymphocytes (PBL) by ...oncoretroviral and lentiviral vectors. In the oncoretroviral vector, the green fluorescent protein (GFP) reporter gene was regulated by the murine stem cell virus (MSCV) promoter. In three human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors, the GFP transgene was regulated by either a chimeric MSCV/HIV-1 promoter, or cellular promoters from human housekeeping genes PGK and EF1 alpha. We found that several lines of proliferating tumor-specific CTL were poorly (=2%) transduced by the oncoretroviral vector that transduced Jurkat T cell line efficiently (=80%). In contrast, three lentiviral vectors transduced 38-63% of these proliferating CTL. More interestingly, all lentiviral vectors packaged without the HIV-1 accessory proteins transduced human bulk PBL and purified CD4(+) and CD8(+) lymphocyte subsets without prior stimulation. Detailed analysis indicated that the lentiviral vectors containing the EF1 alpha or PGK ubiquitous promoter can transduce unstimulated PBL and achieve low-level transgene expression in the absence of any T-cell activation. However, T-cell activation subsequent to the transduction of unstimulated PBL is required for high-level transgene expression. Transduced PBL expressing transgene delivered by the lentiviral vectors still preserved resting and naïve cell phenotypes. Taken together, prior T cell stimulation and HIV-1 accessory proteins are dispensable for lentivirus-mediated gene transfer into resting naïve and memory T lymphocytes. These results will have significant implications for the study of T-cell biology and for the improvement of clinical gene therapies of acquired immune deficiency syndrome (AIDS) and cancer.
Immunotherapy of Cancer JAFFEE, ELIZABETH M.
Annals of the New York Academy of Sciences,
01/1999, Letnik:
886, Številka:
1
Journal Article
Recenzirano
: The goal of cancer treatment is to develop modalities that specifically target tumor cells, thereby avoiding unnecessary side effects to normal tissue. Vaccine strategies that result in the ...activation of the immune system specifically against proteins expressed by a cancer have the potential to be effective treatment for this purpose. An early vaccine approach that was developed by our group involves the insertion of the granulocyte‐macrophage colony stimulating factor (GM‐CSF) gene into cancer cells that are then used to immunize patients. These genetically modified tumor cells produce the immune activating protein GM‐CSF in the local environment of the tumor cells, specifically activating the patient's T cells to eradicate cancer at metastatic sites. We have performed many studies that demonstrate that this vaccine can cure mice of cancer. We recently demonstrated that this approach can activate an immune response in patients with renal cell carcinoma. We are currently testing a similar approach in patients with pancreatic cancer. Until recently, whole tumor cells were used to produce the vaccine because the proteins expressed by the tumor cells that can be recognized by the immune system were unknown. However, recent advances have allowed the identifiation of many of the proteins expressed by some cancers. In addition, significant attention has been focused on the mechanisms by which antitumor immunity can be modulated. These active areas of research will undoubtably lead to the devleopment of more specific and more potent vaccine strategies in the near future. The first part of this paper focuses on data from two recent clinical trials that evaluated the whole tumor cell approach. The second part of this paper discusses some of the more exciting antigen‐specific vaccine approaches that are under development for the treatment of cancer.
Keywords: pancreatic cancer, patient-derived organoids, transcriptomic signatures, PASS-01 Background: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) continue to have a dire prognosis ...and only a minority of patients is fit enough to receive second-line treatment. Secondary and exploratory objectives include determine the objective response rate, duration of response and overall survival associated with mFFX or GA, whether the chemotherapy sensitivity signature predictions correlate with responders, if PDO transcriptomic profiles parallel those obtained from patient samples, whether GATA6 expression can serve as a biomarker of response 4, the use of serial cell free circulating tumor DNA and circulating tumour cell analysis to identify emerging or de novo resistance and evaluate biomarkers of immune-oncologic sensitivity. At progression, as per RECIST 1.1 criteria, chemotherapy sensitivity signatures (RNA) and/or PDO pharmacotyping and WGS data will be used where possible to guide second-line therapy in an effort to continually provide the most active therapeutic regimens to each patient.
The aggressiveness of pancreatic ductal adenocarcinoma (PDA) is characterized by its high metastatic potential and lack of effective therapies, which is the result of a lack of understanding of the ...mechanisms involved in promoting PDA metastases. We identified Annexin A2 (ANXA2), a member of the Annexin family of calcium-dependent phospholipid binding proteins, as a new molecule that promotes PDA invasion and metastases. We found ANXA2 to be a PDA-associated antigen recognized by post-treatment sera of patients who demonstrated prolonged survival following treatment with a PDA-specific vaccine. Cell surface ANXA2 increases with PDA development and progression. Knockdown of ANXA2 expression by RNA interference or blocking with anti-ANXA2 antibodies inhibits in vitro invasion of PDA cells. In addition, post-vaccination patient sera inhibits in vitro invasion of PDA cells, suggesting that therapeutic anti-ANXA2 antibodies are induced by the vaccine. Furthermore, cell-surface localization of ANXA2 is tyrosine 23 phosphorylation-dependent; and tyrosine 23 phosphorylation is required for PDA invasion. We demonstrated that tyrosine 23 phosphorylation resulting in surface expression of ANXA2 is required for TGFβ-induced, Rho-mediated epithelial-mesenchymal transition (EMT), linking the cellular function of ANXA2 which was previously shown to be associated with small GTPase-regulated cytoskeletal rearrangements, to the EMT process in PDA. Finally, using mouse PDA models, we showed that shRNA knock-down of ANXA2, a mutation at tyrosine 23, or anti-ANXA2 antibodies, inhibit PDA metastases and prolong mouse survival. Thus, ANXA2 is part of a novel molecular pathway underlying PDA metastases and a new target for development of PDA therapeutics.
Background Wheezing illnesses cause major morbidity in infants and are frequent precursors to asthma. Objective We sought to examine environmental factors associated with recurrent wheezing in ...inner-city environments. Methods The Urban Environment and Childhood Asthma study examined a birth cohort at high risk for asthma (n = 560) in Baltimore, Boston, New York, and St Louis. Environmental assessments included allergen exposure and, in a nested case-control study of 104 children, the bacterial content of house dust collected in the first year of life. Associations were determined among environmental factors, aeroallergen sensitization, and recurrent wheezing at age 3 years. Results Cumulative allergen exposure over the first 3 years was associated with allergic sensitization, and sensitization at age 3 years was related to recurrent wheeze. In contrast, first-year exposure to cockroach, mouse, and cat allergens was negatively associated with recurrent wheeze (odds ratio, 0.60, 0.65, and 0.75, respectively; P ≤ .01). Differences in house dust bacterial content in the first year, especially reduced exposure to specific Firmicutes and Bacteriodetes, was associated with atopy and atopic wheeze. Exposure to high levels of both allergens and this subset of bacteria in the first year of life was most common among children without atopy or wheeze. Conclusions In inner-city environments children with the highest exposure to specific allergens and bacteria during their first year were least likely to have recurrent wheeze and allergic sensitization. These findings suggest that concomitant exposure to high levels of certain allergens and bacteria in early life might be beneficial and suggest new preventive strategies for wheezing and allergic diseases.
Background
Use of the immune checkpoint inhibitor ipilimumab is sometimes complicated by ipilimumab‐associated colitis (Ipi‐AC), an immune‐mediated colitis that mimics inflammatory bowel disease.
...Objective
We sought to characterize the histopathologic and immunophenotypic features of Ipi‐AC and to directly compare these features to ulcerative colitis (UC).
Methods
This is a retrospective cohort study of 22 patients with Ipi‐AC, 12 patients with treatment‐naïve UC and five controls with diarrhoea but normal endoscopic findings. Immunohistopathologic features were described, and quantitative immunohistochemistry (IHC) was performed for CD4, CD8, CD20, CD138 and FOXP3.
Results
Endoscopic findings in both the Ipi‐AC and UC groups included ulcerated, oedematous and erythematous mucosa. Involvement of the GI tract was more diffuse in Ipi‐AC. As compared to UC, a smaller proportion of Ipi‐AC biopsies had basal plasmacytosis (14% for Ipi‐AC vs. 92% for UC, P < 0.0001) and crypt distortion (23% for Ipi‐AC vs. 75% for UC, P = 0.003), whereas Ipi‐AC biopsies had more apoptotic bodies in the left colon (17.6 ± 15.3 for Ipi‐AC vs. 8.2 ± 4.2 for UC, P = 0.011). Cryptitis, ulcerations and crypt abscesses were common in both groups. Biopsy specimens from Ipi‐AC had a lower density of CD20‐positive lymphocytes than UC (275.8 ± 253.3 cells mm−2 for Ipi‐AC vs. 1173.3 ± 1158.2 cells mm−2 for UC, P = 0.022) but had a similar density of CD4, CD8, CD138 and FOXP3‐positive cells.
Conclusions
Ipi‐AC is a distinct pathologic entity with notable clinical and histopathological differences compared to UC. These findings provide insights into the pathophysiology of immune‐related adverse events (iAEs) from ipilimumab therapy.
Introduction of the B7-1 gene into murine tumor cells can result in rejection of the B7-1 transductants and, in some cases, systemic immunity to subsequent challenge with the nontransduced tumor ...cells. These effects have been largely attributed to the function of B7-1 as a costimulator in directly activating tumor specific, major histocompatibility class I-restricted CD8+ T cells. We examined the role of B7-1 expression in the direct rejection as well as in the induction of systemic immunity to a nonimmunogenic murine tumor. B-16 melanoma cells with high levels of B7-1 expression did not grow in C57BL/6 recipient mice, while wild-type B-16 cells and cells with low B7-1 expression grew progressively within 21 d. In mixing experiments with B7-1hi and wild-type B-16 cells, tumors grew out in vivo even when a minority of cells were B7-1-. Furthermore, the occasional tumors that grew out after injection of 100% B-16 B7-1hi cells showed markedly decreased B7-1 expression. In vivo antibody depletions showed that NK1.1 and CD8+ T cells, but not CD4+ T cells, were essential for the in vivo rejection of tumors. Animals that rejected B-16 B7-1hi tumors did not develop enhanced systemic immunity against challenge with wild-type B-16 cells. These results suggest that a major role of B7-1 expression by tumors is to mediate direct recognition and killing by natural killer cells. With an intrinsically nonimmunogenic tumor, this direct killing does not lead to enhanced systemic immunity.
Published series on COVID-19 support the notion that patients with cancer are a particularly vulnerable population. There is a confluence of risk factors between cancer and COVID-19, and cancer care ...and treatments increase exposure to the virus and may dampen natural immune responses. The available evidence supports the conclusion that patients with cancer, in particular with hematologic malignancies, should be considered among the very high-risk groups for priority COVID-19 vaccination.
Preclinical studies with murine tumor models have demonstrated that autologous tumor cell vaccines engineered to secrete certain cytokines in a paracrine fashion elicit systemic immune responses ...capable of eliminating small amounts of established tumor. These results have engendered much interest in developing this strategy for gene therapy of human cancer. The major limitation to creating genetically modified autologous human tumor vaccines is efficient gene transfer into primary tumor explants, since the majority of human tumors fail to proliferate in long-term culture. Using the retroviral vector MFG in conjunction with short-term culture techniques, we have achieved, in the absence of selection, a mean transduction efficiency of 60% in primary renal, ovarian, and pancreatic tumor explants, and we have developed an autologous granulocyte-macrophage colony-stimulating factor secreting tumor vaccine for clinical trials.
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