Azam V. Nahvi

Bio: Azam V. Nahvi is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Immunotherapy & Adoptive cell transfer. The author has an hindex of 7, co-authored 7 publications receiving 4413 citations.

Cancer regression in patients after transfer of genetically engineered lymphocytes

Abstract: Through the adoptive transfer of lymphocytes after host immunodepletion, it is possible to mediate objective cancer regression in human patients with metastatic melanoma. However, the generation of tumor-specific T cells in this mode of immunotherapy is often limiting. Here we report the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least 2 months after the infusion. We observed high sustained levels of circulating, engineered cells at 1 year after infusion in two patients who both demonstrated objective regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of cancer.

Tumor Regression in Patients With Metastatic Synovial Cell Sarcoma and Melanoma Using Genetically Engineered Lymphocytes Reactive With NY-ESO-1

Abstract: Purpose Adoptive immunotherapy using tumor-infiltrating lymphocytes represents an effective cancer treatment for patients with metastatic melanoma. The NY-ESO-1 cancer/testis antigen, which is expressed in 80% of patients with synovial cell sarcoma and approximately 25% of patients with melanoma and common epithelial tumors, represents an attractive target for immune-based therapies. The current trial was carried out to evaluate the ability of adoptively transferred autologous T cells transduced with a T-cell receptor (TCR) directed against NY-ESO-1 to mediate tumor regression in patients with metastatic melanoma and synovial cell sarcoma.

A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma.

Abstract: Immunotherapeutic approaches to patients with metastatic melanoma are based on developing lymphocytes with the ability to recognize and destroy tumor cells High-dose interleukin (IL)-2 therapy is capable of inducing durable, complete responses in a subset of patients with melanoma (1,2) and is thought to act through T lymphocytes to mediate tumor eradication Direct evidence for the antitumor capacity of T cells in patients with melanoma comes from studies in which lymphocytes were isolated directly from resected tumor specimens, expanded with IL-2 in vitro, and administered to patients for therapy These tumor-infiltrating lymphocytes (TIL), when administered together with high-dose IL-2, produced objective tumor regressions in 34% of treated patients including patients refractory to IL-2 therapy (3) Many genes encoding tumor antigens that are recognized by T cells have been cloned, and the HLA-restricted peptide epitopes derived from them have been identified (4) Clinical evaluation of the immunogenicity and therapeutic efficacy of modified peptide epitopes from gp100 and other melanoma-melanocyte differentiation antigens (5,6) is currently underway Administration of the anchor-modified gp100:209–217(210M) peptide (referred to as g209–2M) in incomplete Freund’s adjuvant in combination with IL-2 therapy resulted in objective clinical responses in 13 of 31 patients (42%) (7) The g209–2M peptide has been shown to be highly immunogenic, inducing specific T-cell responses that comprised up to 1% of peripheral blood CD8+ lymphocytes (8) Cloning and evaluation of lymphocytes from patients vaccinated with the g209–2M peptide showed that the induced T-cell response was heterogeneous and included T cells that were highly avid for the native g209 peptide as well as strongly reactive with HLA-A2 matched melanoma cell lines (9,10) These results have led to the further evaluation of g209–2M and other tumor antigens for the therapy of patients with melanoma and other cancers The ability to routinely immunize patients using peptide vaccination provided the rationale for re-examining T-cell transfer as a therapeutic modality, and in a previous study, we reported on the isolation and in vitro expansion of peptide-specific, tumor-reactive T-cell clones from immunized patients for adoptive therapy (11) Thirteen patients were treated with multiple cycles of highly avid T-cell clones, with or without concomitant high-dose IL-2 Although the treatment was safe and well tolerated, no objective clinical responses were noted Significantly, analysis of peripheral blood samples of treated patients revealed that the transferred clones disappeared rapidly from the circulation and decreased to undetectable levels within 1 week of transfer Similarly, radionuclide labeling of aliquots of infused cells provided no evidence for traffic of transferred clones to tumor deposits This study reports on the use of a nonmyeloablative chemotherapy regimen before the adoptive transfer of cloned T cells for the therapy of patients with metastatic melanoma This study was initiated based on the indirect evidence from clinical trials and direct evidence from preclinical model systems that immune suppression may enhance the efficacy of lymphocyte transfer therapy Fifteen patients with malignant melanoma were treated The trial was designed as a phase I dose-escalation study to evaluate the toxicity of the multi-modality treatment that included immunosuppressive chemotherapy, T-cell transfer, and IL-2 administration Hematologic effects of the combination therapy, as well as nonhematologic toxicities and clinical responses were evaluated

Tumor Infiltrating Lymphocytes Genetically Engineered with an Inducible Gene Encoding Interleukin-12 for the Immunotherapy of Metastatic Melanoma

Abstract: Purpose: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Experimental Design: Thirty-three patients with metastatic melanoma were treated in a cell dose–escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT.IL12). No IL2 was administered. Results: The administration of 0.001 to 0.1 × 10 9 NFAT.IL12–transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 10 9 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNγ as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. Conclusions: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients. Clin Cancer Res; 21(10); 2278–88. ©2015 AACR .

Relationship of p53 overexpression on cancers and recognition by anti-p53 T cell receptor-transduced T cells.

Abstract: Tumor suppressor p53 is reported to be an attractive immunotherapy target because it is mutated in approximately half of human cancers, resulting in inactivation and often an accumulation of the protein in the tumor cells. Only low amounts of protein are detectable in normal tissues. The differential display of antigen in normal versus tumor tissues has been reported to create an opportunity to target p53 by immunotherapy. We sought to determine the relationship between p53 expression and its recognition by cognate T cells in human tumors including common epithelial malignancies. Inasmuch as nonsense or missense p53 mutations may disrupt processing and presentation, we studied tumors with either identified wild-type or mutated p53, based on our gene-sequencing studies or published data. T cells transduced with a high-affinity, p53264–272-reactive T cell receptor (TCR) derived from HLA-A2.1 transgenic mice recognized a wide panel of human tumor lines. There was no significant correlation between p53 expression in tumors and recognition by the anti-p53 TCR-transduced T cells. This conclusion was based on the study of 48 cell lines and is in contrast to several prior studies that used only a limited number of selected cell lines. A panel of normal cells was evaluated for recognition, and some of these populations were capable of stimulating anti-p53 T cells, albeit at low levels. These studies raise doubts concerning the suitability of targeting p53 in the immunotherapy of cancer patients.

Cancer immunotherapy comes of age

Abstract: Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. After decades of disappointment, the tide has finally changed due to the success of recent proof-of-concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody, ipilimumab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together with the advent of targeted therapies, these successes suggest that active immunotherapy represents a path to obtain a durable and long-lasting response in cancer patients.

Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes

Abstract: We report here the adoptive transfer, to patients with metastatic melanoma, of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen. This approach resulted in the persistent clonal repopulation of T cells in those cancer patients, with the transferred cells proliferating in vivo, displaying functional activity, and trafficking to tumor sites. This led to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction. This approach presents new possibilities for the treatment of patients with cancer as well as patients with human immunodeficiency virus-related acquired immunodeficiency syndrome and other infectious diseases.

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

Abstract: BackgroundApproximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. MethodsWe analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti–PD-1 therapy (pembrolizumab) followed by disease progression months to years later. ResultsWhole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-m...