Failure to define window of time for autologous tumor vaccination in patients with newly diagnosed or relapsed acute lymphoblastic leukemia

Haining, W. Nicholas; Cardoso, Angelo A.; Keczkemethy, Heather L.; Fleming, Mark D.; Neuberg, Donna; DeAngelo, Daniel J.; Stone, Richard; Galinsky, Ilene; Silverman, Lewis B.; Sallan, Stephen E.; Nadler, Lee M.; Guinan, Eva C.

doi:10.1016/j.exphem.2004.12.001

Cited by 29 publications

(23 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Vaccination against a neo-antigen-hepatitis B-during treatment for ALL has been reported to be unsuccessful in nearly 75% of children. 29 We recently reported a phase 1 tumor vaccine trial in ALL, 30 based on our previous observation that T cells specific for autologous tumor cells can be detected in many children with ALL. [31][32][33] Several groups have also identified epitopes from candidate tumor antigens that could serve as targets for tumor vaccination in ALL.…”

Section: Discussionmentioning

confidence: 99%

Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia

Haining

Neuberg

Keczkemethy

et al. 2005

Blood

Self Cite

View full text Add to dashboard Cite

Despite profound T-cell immunodeficiency, most patients treated with chemotherapy do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. We prospectively measured Tcell numbers, thymopoiesis, and T-cell memory in 73 children undergoing a 2-year chemotherapy regimen for acute lymphoblastic leukemia (ALL) and compared them to an age-matched cohort of 805 healthy children. Most patients had profound defects in CD4 and CD8 T-cell numbers at diagnosis that did not recover during the 2 years of therapy. Thymic output and the fraction of naive T cells were significantly lower than in healthy controls. However, the remaining T-cell compartment was enriched for antigen-experienced, memory T cells defined both by phenotype and by function. This relative sparing of T-cell memory may, in part, account for the maintenance of protective immunity in lymphopenic patients treated for ALL. Moreover, because the memory T-cell compartment is least affected by ALL and its treatment, strategies to induce immunity to pathogens or tumor antigens in cancer patients may be most successful if they seek to expand preexisting memory T cells. IntroductionPatients undergoing chemotherapy for cancer are susceptible to infection, particularly in hematologic malignancies such as acute lymphoblastic leukemia (ALL) where infections account for 80% of remission deaths. [1][2][3] However, while infection represents a significant complication of chemotherapy, the number of patients who succumb to infection is low. For instance, fewer than 1% of children undergoing maintenance therapy for ALL die from infection. 3 Although infection prophylaxis and good supportive care are likely to contribute to this low infectious mortality, the majority of patients with ALL appear to retain protective immunity against infection despite prolonged chemotherapy. The nature of this residual immune function in lymphopenic patients is not known.In the normal host the peripheral T-cell compartment consists of naive T cells, which originate in the thymus, and memory T cells, which have differentiated from naive T cells in response to antigen exposure. Memory T cells can rapidly proliferate and acquire effector function on re-exposure to antigen. Together with antibody response, memory T cells are central to the maintenance of protective immunity. However, the fate of the memory T-cell compartment in patients treated with chemotherapy is poorly understood. Seminal studies by Mackall et al 4-7 described the profound depletion seen in the T-cell compartment following chemotherapy. They showed that intensive chemotherapy is associated with a near-total loss of naive CD4 T cells, which do not reappear until several months after the end of treatment. [4][5][6][7] Recent data using assays that quantify thymic output have also shown a marked decrease in thymic output in patients treated with chemotherapy and radiation, suggesting that direct thymic injury may account for this lack of naive T cells. 8,9 Together, these studies...

show abstract

Section: Discussionmentioning

confidence: 99%

Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia

Haining

Neuberg

Keczkemethy

et al. 2005

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…41 We observed effective CpG ODN-induced elimination of disease progression at blast levels in this range, which is encouraging for the development of immune-based therapies for the treatment of children with highrisk ALL. Whereas the application of immune therapy to patients on standard therapy regimens is thought to be limited by poor immune function and need for reconstitution, 42 the report of significant immune responses by high-risk ALL patients to an autologous vaccine indicates that sufficient immune cell populations are present during this treatment window. The ability of CpG ODN to induce both strong innate and adaptive antileukemia immune activity may render it an appropriate agent for therapeutic application in ALL.…”

Section: Durable Protection From All Induced Bymentioning

confidence: 99%

Long-term protection from syngeneic acute lymphoblastic leukemia by CpG ODN-mediated stimulation of innate and adaptive immune responses

Seif

Barrett

Milone³

et al. 2009

Blood

View full text Add to dashboard Cite

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and remains a major cause of mortality in children with recurrent disease and in adults. Despite observed graft-versusleukemia effects after stem cell transplantation, successful immune therapies for ALL have proven elusive. We previously reported immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG ODN) enhance allogeneic T h 1 responses and reduce leukemic burden of primary human ALL xenografts. To further the development of CpG ODN as a novel ALL therapy, we investigated the antileukemia activity induced by CpG ODN in a transplantable syngeneic pre-B ALL model. CpG ODN induced early killing of leukemia by innate immune effectors both in vitro and in vivo. Mice were treated with CpG ODN starting 7 days after injection with leukemia to mimic a minimal residual disease state and achieved T cell-dependent remissions of more than 6 months. In addition, mice in remission after CpG ODN treatment were protected from leukemia rechallenge, and adoptive transfer of T cells from mice in remission conferred protection against leukemia growth. To our knowledge, this is the first demonstration that CpG ODN induce a durable remission and ongoing immune-mediated protection in ALL, suggesting this treatment may have clinical utility in patients with minimal residual disease. (Blood. 2009;114:2459-2466) IntroductionAcute lymphoblastic leukemia (ALL) is the most common form of cancer in children, accounting for one-third of all childhood malignancies and nearly 80% of all pediatric leukemias. 1 Although current therapies have resulted in event-free survival approaching 75%, 2 relapsed ALL comprises nearly 6% of all childhood cancers 1,3 and has a much lower event-free survival of 47%. 4 Furthermore, nearly half of all ALL cases occur in adults, who have a much poorer prognosis, with the majority dying of the disease. 5 New treatment strategies are urgently needed for this condition.The strategy of pursuing immune therapy as a novel therapeutic approach for ALL is supported by the observed graft-versusleukemia effect after hematopoietic stem cell transplantation. Although transplantations and donor lymphocyte infusions have lower efficacy in ALL than in other leukemias, the consistently higher relapse rates associated with autologous and especially syngeneic transplantations compared with allogeneic transplantations are supportive of significant therapeutic immune activity. [6][7][8][9] In pediatric transplantations, the development of chronic graft-versushost disease correlates strongly with decreased relapse. 8 Furthermore, posttransplantation immune suppression is associated with an increased risk of relapse. 10 Despite evidence of a graft-versus-leukemia effect against ALL, enhancing the anti-ALL immune response has proven difficult to achieve. Several features of ALL may undermine the immune system's ability to mount a targeted response, including a lack of costimulatory molecule expression, 11,12 the impairment of dendritic cell (DC) antige...

show abstract

“…Although antileukemia CTL can be elicited in vitro by modified leukemia cells or dendritic cell-based strategies (5, 9), the rapid progression of the disease and its associated lymphopenia may preclude the clinical use of autologous tumor cell vaccination in relapsed ALL (41). An alternative strategy could be the ex vivo amplification of antileukemia T cells and their adoptive transfer into patients.…”

Section: Bax-d As a Novel Leukemia Tumor Antigenmentioning

confidence: 99%

Gene Expression Profiling IdentifiesBAX-δas a Novel Tumor Antigen in Acute Lymphoblastic Leukemia

et al. 2005

Self Cite

View full text Add to dashboard Cite

The identification of new tumor-associated antigens (TAA) is critical for the development of effective immunotherapeutic strategies, particularly in diseases like B-cell acute lymphoblastic leukemia (B-ALL), where few target epitopes are known. To accelerate the identification of novel TAA in B-ALL, we used a combination of expression profiling and reverse immunology. We compared gene expression profiles of primary B-ALL cells with their normal counterparts, B-cell precursors. Genes differentially expressed by B-ALL cells included many previously identified as TAA in other malignancies. Within this set of overexpressed genes, we focused on those that may be functionally important to the cancer cell. The apoptosis-related molecule, BAX, was highly correlated with the ALL class distinction. Therefore, we evaluated BAX and its isoforms as potential TAA. Peptides from the isoform BAX-D bound with high affinity to HLA-A*0201 and HLA-DR1.

show abstract

Failure to define window of time for autologous tumor vaccination in patients with newly diagnosed or relapsed acute lymphoblastic leukemia

Cited by 29 publications

References 50 publications

Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia

Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia

Long-term protection from syngeneic acute lymphoblastic leukemia by CpG ODN-mediated stimulation of innate and adaptive immune responses

Gene Expression Profiling IdentifiesBAX-δas a Novel Tumor Antigen in Acute Lymphoblastic Leukemia

Contact Info

Product

Resources

About