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Among clinicians, initial awareness of the Wilms' tumor gene was limited mostly to pediatric oncologists. Almost a decade ago, overexpression of Wilms' tumor 1 (WT1) was observed in adult acute leukemia. Subsequent studies indicated that WT1 overexpression occurs in most cases of acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). Limited tissue expression of WT1 in adults suggests that WT1 can be a target for leukemia/MDS therapy. WT1 expression in stem/progenitor cells remains unsettled. However, lack of progenitor cell suppression by WT1 antisense or WT1-specific cytotoxic T cells provide some assurance that WT1 expression in progenitor cells is minimal or absent. Immunotherapy-based WT1 approaches are furthest along in preclinical development. WT1-specific cytotoxic lymphocytes can be generated from normals and leukemic patients. In mice, WT1 vaccines elicit specific immune responses without evidence of tissue damage. In this paper, we review studies validating the immunogenicity of WT1 and propose that leukemia and MDS may be a good clinical model to test the efficacy of a WT1 vaccine.

With the ultimate goal of developing a therapeutic cancer vaccine, we encapsulated the Her-2/neu peptide p369–377 in poly(lactide-co-glycolide) microspheres. This formulation was found to effectively elicit CD8+ cytotoxic T cell (CTL) responses in an HLA-A*0201 transgenic mouse model. In contrast, immunization with either peptide alone or peptide formulated in incomplete Freund's adjuvant (IFA) failed to elicit such CTL responses. Responses induced by the peptide-microsphere formulation were found to peak at approximately 6 weeks post-immunization, and were enhanced by delivering increased doses of peptide and with repeated administrations over time. Co-administration of the peptide-microspheres with adjuvants, including granulocyte–macrophage colony stimulating factor, MPL ® adjuvant and select synthetic Toll-Like Receptor 4 ligands, the aminoalkyl glucosaminide-4 phosphates, significantly augmented CTL responses. These studies provide important guidance for the design of human clinical trials of microsphere vaccines in terms of optimal peptide-microsphere formulation, vaccination regimen, vaccine dose, and adjuvant selection.

The hallmark of chronic myelogenous leukemia is the translocation of the human c-abl protooncogene (ABL) from chromosome 9 to the specific breakpoint cluster region (bcr) of the BCR gene on chromosome 22. The t(9;22)(q34;q11) translocation results in the formation of a BCR-ABL fusion gene that encodes a 210-kDa chimeric protein with abnormal tyrosine kinase activity. The ABL and BCR genes are expressed by normal cells and thus the encoded proteins are presumably nonimmunogenic. However, the joining-region segment of the p210BCR-ABL chimeric protein is composed of unique sequences of ABL amino acids joined to BCR amino acids that are expressed only by malignant cells. The current study demonstrates that the joining region of BCR-ABL protein is immunogenic to murine T cells. Immunization of mice with synthetic peptides corresponding to the joining region elicited peptide-specific, CD4+, class II major histocompatibility complex-restricted T cells. The BCR-ABL peptide-specific T cells recognized only the combined sequence of BCR-ABL amino acids and not BCR or ABL amino acid sequences alone. Importantly, the BCR-ABL peptide-specific T cells could recognize and proliferate in response to p210BCR-ABL protein. The response of peptide-specific T cells to protein demonstrated that p210BCR-ABL can be processed by antigen-presenting cells so that the joining segment is bound to class II major histocompatibility complex molecules in a configuration similar to that of the immunizing peptide and in a concentration high enough to stimulate the antigen-specific T-cell receptor. Thus, BCR-ABL protein represents a potential tumor-specific antigen related to the transforming event and shared by many individuals with chronic myelogenous leukemia.

Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.

The bispecific monoclonal antibody (bsmAb) 2B1, targeting the extracellular domain of c-erbB-2, the protein product of the HER-2/neu proto-ocogene, and Fc gamma RIII (CD16), expressed by human natural killer cells, neutrophils and differentiated monocytes, mediates the specific cytotoxic activity of these effector cells to tumor cells. A group of 24 patients with c-erbB-2-overexpressing tumors were treated with intravenously administered 2B1 in a phase I clinical trial and followed after treatment to evaluate the diversity and extent of the 2B1-induced humoral immune responses. As expected, 17 of 24 patients developed human anti-(murine Ig) antibodies (HAMA) to whole 2B1 IgG in a range from 100 ng/ml to more than 50000 ng/ml; 10 of these patients (42%) had strong (at least 1000 ng/ml) HAMA responses, some of which were still detectable at day 191. These responses were usually associated with similar reactivity to the F(ab')2 fragments of the parental antibodies 520C9 (anti-c-erbB-2) and 3G8 (anti-CD16). We sought evidence of an idiotypic cascade induction, indicating a prolonged specific treatment-induced effect on at least one selected target of 2B1. Using competition-based enzyme-linked immunosorbent assays, specific anti-idiotypic antibodies (Ab2) were detectable against 520C9 in 11 patients and against 3G8 in 13 patients. Peak anti-idiotypic antibodies generally occurred 3-5 weeks from treatment initiation, with a downward trend thereafter. There was a statistically significant correlation among the induction of significant HAMA responses, anti-idiotypic antibody production and the development of antibodies to c-erbB-2. The anti-c-erbB-2 responses, which were distinct from anti-anti-idiotypic (Ab3) antibodies, were detected in the post-treatment sera of 6/16 patients examined. No obvious correlation could be made between the development of humoral immune responses, the dose received, and the clinical response. Future investigation involving 2B1 therapy will concentrate on investigating an association of these humoral responses to any c-erbB-2-specific cellular responses. Manipulations of 2B1 therapy effects that augment immunity to c-erbB-2 could provide additional avenues for immunotherapy with this and other bispecific antibodies.

L523S is an immunogenic lung cancer antigen that has demonstrated preclinical safety when the gene is injected intramuscularly as an expressive plasmid (pVAX/L523S) and when delivered following incorporation into an E1B-deleted adenovirus (Ad/L523S). We performed a phase I clinical trial in 13 stage IB, IIA, and IIB non-small-cell lung cancer patients. pVAX/L523S (8 mg on days 0 and 14 in all cohorts) and Ad/L523S (1, 20, 400 x 10(9) vp on days 28 and 56, cohorts 1, 2, and 3, respectively) were administered to 3 patients in each of three cohorts. No significant toxic effect was identified. All but 1 patient demonstrated greater than or equal to twofold elevation in anti-adenovirus antibodies. One of 10 evaluable patients demonstrated L523S-specific antibody by direct IgG ELISA. Two patients developed disease recurrence and all remain alive after a median of 290 days follow-up. Results suggest a high level of safety but evidence of L523S-directed immune activation was limited, suggesting a need for modification of dose, schedule, and site of vaccination (i.e., intradermal) with further clinical testing.

Among clinicians, initial awareness of the Wilms' tumor gene was limited mostly to pediatric oncologists. Almost a decade ago, overexpression of Wilms' tumor 1 (WT1) was observed in adult acute leukemia. Subsequent studies indicated that WT1 overexpression occurs in most cases of acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). Limited tissue expression of WT1 in adults suggests that WT1 can be a target for leukemia/MDS therapy. WT1 expression in stem/progenitor cells remains unsettled. However, lack of progenitor cell suppression by WT1 antisense or WT1-specific cytotoxic T cells provide some assurance that WT1 expression in progenitor cells is minimal or absent. Immunotherapy-based WT1 approaches are furthest along in preclinical development. WT1-specific cytotoxic lymphocytes can be generated from normals and leukemic patients. In mice, WT1 vaccines elicit specific immune responses without evidence of tissue damage. In this paper, we review studies validating the immunogenicity of WT1 and propose that leukemia and MDS may be a good clinical model to test the efficacy of a WT1 vaccine.

Research efforts over the last two decades studying immune responses to human carcinomas have demonstrated that antigens expressed by tumor cells can elicit specific cellular and humoral immune responses. Unfortunately, despite the observation that existent immune responses to these antigens are present in some patients with cancer, the tumors continue to progress. Thus, there has been considerable interest to augment these immune responses by immunization. Some of the clinical trials of the first cancer vaccines have provided evidence of clinical benefit thus encouraging the development of other vaccines. Challenges to development of such cancer vaccines include the identification and characterization of the antigen(s) to be targeted, the definition of the desired immune response to be elicited by the vaccine, and the choice of the appropriate vaccine delivery system.

Twelve patients in the chronic phase of Ph 1 (Philadelphia)-positive chronic granulocytic leukemia (CGL) received chemoradiotherapy and marrow from their normal, identical twins. All had a complete remission, with disappearance of all Ph 1 -positive cells. One patient died of pneumonitis while in remission. Three had a cytogenetic relapse 22 to 30 months after grafting; only one of these three entered blast crisis and died. Eight remain in complete remission 21 to 65 months (median, 30) after transplantation. Thus, the Ph 1 -positive clone can be ablated and blast crisis delayed or prevented. Of 10 patients with CGL who received transplants during the terminal phase, eight died soon after, one is in complete remission 11 months after receiving a second graft, and one remains in complete remission 71 months after transplantation. This experience suggests to us that every patient with CGL and an identical twin should receive a marrow graft, preferably in the chronic phase. On the basis of our results, trials of allogeneic-marrow transplantation for CGL seem justified. (N Engl J Med. 1982; 306:63–8.) Chronic granulocytic leukemia (CGL) is associated with a median survival time of two to four years, with few long-term survivors and no cures. 1 It usually terminates in blast crisis — at times preceded by a brief accelerated phase — which is generally refractory to chemotherapy and fatal within a few months. 2 Conventional therapy given during the chronic phase of CGL has not influenced the development of the terminal phase and has had no appreciable effect on survival. 1 , 2 Treatment of chronic-phase CGL with more aggressive chemotherapy has been explored in an effort to eradicate the abnormal Philadelphia (Ph 1 )-positive clone and . . .