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Combination of Id2 Knockdown Whole Tumor Cells and Checkpoint Blockade: A Potent Vaccine Strategy in a Mouse Neuroblastoma Model.

Chakrabarti L, Morgan C, Sandler AD - PLoS ONE (2015)

Bottom Line: Tumor vaccines have held much promise, but to date have demonstrated little clinical success.Id2-kd N2a cells grew aggressively in immune-compromised hosts, thereby establishing the immunogenicity of these cells.Mechanistically, immune cell depletion studies demonstrated that while CD8+ T cells are critical for antitumor immunity, CD4+ T cells are also required to induce a sustained long-lasting helper effect.

View Article: PubMed Central - PubMed

Affiliation: The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, George Washington University, Washington, District of Columbia, United States of America.

ABSTRACT
Tumor vaccines have held much promise, but to date have demonstrated little clinical success. This lack of success is conceivably due to poor tumor antigen presentation combined with immuno-suppressive mechanisms exploited by the tumor itself. Knock down of Inhibitor of differentiation protein 2 (Id2-kd) in mouse neuroblastoma whole tumor cells rendered these cells immunogenic. Id2-kd neuroblastoma (Neuro2a) cells (Id2-kd N2a) failed to grow in most immune competent mice and these mice subsequently developed immunity against further wild-type Neuro2a tumor cell challenge. Id2-kd N2a cells grew aggressively in immune-compromised hosts, thereby establishing the immunogenicity of these cells. Therapeutic vaccination with Id2-kd N2a cells alone suppressed tumor growth even in established neuroblastoma tumors and when used in combination with immune checkpoint blockade eradicated large established tumors. Mechanistically, immune cell depletion studies demonstrated that while CD8+ T cells are critical for antitumor immunity, CD4+ T cells are also required to induce a sustained long-lasting helper effect. An increase in number of CD8+ T-cells and enhanced production of interferon gamma (IFNγ) was observed in tumor antigen stimulated splenocytes of vaccinated mice. More importantly, a massive influx of cytotoxic CD8+ T-cells infiltrated the shrinking tumor following combined immunotherapy. These findings show that down regulation of Id2 induced tumor cell immunity and in combination with checkpoint blockade produced a novel, potent, T-cell mediated tumor vaccine strategy.

No MeSH data available.


Related in: MedlinePlus

Combination of Id2kd N2a and α-CTLA4 antibody as a therapeutic vaccine.(A) Schematic diagram of the therapeutic vaccine strategy. Two established tumor models, namely Neuro2a (wtN2a) and AgN2a were tested, where mice challenged with either wtN2a or AgN2a cells were subjected to a combination immunotherapy with Id2kdN2a and α-CTLA4 antibody starting at day 6 after inoculation. Neuroblastoma tumors are normally visible (5mm in diameter) in AJ mice by day 6. Tumor growth curves in individual mice of wtN2a (B) and AgN2a (C) cells show that the Id2kd tumor cell vaccination combined with immune-modulation cures mice with established tumor. Parentheses indicate the number of mice that survived tumor free.
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pone.0129237.g003: Combination of Id2kd N2a and α-CTLA4 antibody as a therapeutic vaccine.(A) Schematic diagram of the therapeutic vaccine strategy. Two established tumor models, namely Neuro2a (wtN2a) and AgN2a were tested, where mice challenged with either wtN2a or AgN2a cells were subjected to a combination immunotherapy with Id2kdN2a and α-CTLA4 antibody starting at day 6 after inoculation. Neuroblastoma tumors are normally visible (5mm in diameter) in AJ mice by day 6. Tumor growth curves in individual mice of wtN2a (B) and AgN2a (C) cells show that the Id2kd tumor cell vaccination combined with immune-modulation cures mice with established tumor. Parentheses indicate the number of mice that survived tumor free.

Mentions: Encouraged by the effectiveness of this prophylactic model, we reasoned that the combination of the Id2-kd N2a vaccine platform with anti-CTLA-4 antibody may break tolerance even in the presence of large established tumors and induce potent T-cell immunity. We thus examined the combined vaccine/immunotherapy effect in an established neuroblastoma tumor model (Fig 3A). Combined therapy eradicated 60% of established Neuro2a tumors in the wild-type model (Fig 3B) and 90% in AgN2a (aggressive non-immunogenic) model (Figs 3C, 4A and 4B), whereas, CTLA-4 blockade alone resulted in 40% tumor regression in the Neuro2a model and had no effect on tumor growth in the AgN2a model (Fig 3B and 3C). Of interest, again none of the mice developed tumor at the site of Id2-kd N2a cell injection in this established tumor model.


Combination of Id2 Knockdown Whole Tumor Cells and Checkpoint Blockade: A Potent Vaccine Strategy in a Mouse Neuroblastoma Model.

Chakrabarti L, Morgan C, Sandler AD - PLoS ONE (2015)

Combination of Id2kd N2a and α-CTLA4 antibody as a therapeutic vaccine.(A) Schematic diagram of the therapeutic vaccine strategy. Two established tumor models, namely Neuro2a (wtN2a) and AgN2a were tested, where mice challenged with either wtN2a or AgN2a cells were subjected to a combination immunotherapy with Id2kdN2a and α-CTLA4 antibody starting at day 6 after inoculation. Neuroblastoma tumors are normally visible (5mm in diameter) in AJ mice by day 6. Tumor growth curves in individual mice of wtN2a (B) and AgN2a (C) cells show that the Id2kd tumor cell vaccination combined with immune-modulation cures mice with established tumor. Parentheses indicate the number of mice that survived tumor free.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4469424&req=5

pone.0129237.g003: Combination of Id2kd N2a and α-CTLA4 antibody as a therapeutic vaccine.(A) Schematic diagram of the therapeutic vaccine strategy. Two established tumor models, namely Neuro2a (wtN2a) and AgN2a were tested, where mice challenged with either wtN2a or AgN2a cells were subjected to a combination immunotherapy with Id2kdN2a and α-CTLA4 antibody starting at day 6 after inoculation. Neuroblastoma tumors are normally visible (5mm in diameter) in AJ mice by day 6. Tumor growth curves in individual mice of wtN2a (B) and AgN2a (C) cells show that the Id2kd tumor cell vaccination combined with immune-modulation cures mice with established tumor. Parentheses indicate the number of mice that survived tumor free.
Mentions: Encouraged by the effectiveness of this prophylactic model, we reasoned that the combination of the Id2-kd N2a vaccine platform with anti-CTLA-4 antibody may break tolerance even in the presence of large established tumors and induce potent T-cell immunity. We thus examined the combined vaccine/immunotherapy effect in an established neuroblastoma tumor model (Fig 3A). Combined therapy eradicated 60% of established Neuro2a tumors in the wild-type model (Fig 3B) and 90% in AgN2a (aggressive non-immunogenic) model (Figs 3C, 4A and 4B), whereas, CTLA-4 blockade alone resulted in 40% tumor regression in the Neuro2a model and had no effect on tumor growth in the AgN2a model (Fig 3B and 3C). Of interest, again none of the mice developed tumor at the site of Id2-kd N2a cell injection in this established tumor model.

Bottom Line: Tumor vaccines have held much promise, but to date have demonstrated little clinical success.Id2-kd N2a cells grew aggressively in immune-compromised hosts, thereby establishing the immunogenicity of these cells.Mechanistically, immune cell depletion studies demonstrated that while CD8+ T cells are critical for antitumor immunity, CD4+ T cells are also required to induce a sustained long-lasting helper effect.

View Article: PubMed Central - PubMed

Affiliation: The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, George Washington University, Washington, District of Columbia, United States of America.

ABSTRACT
Tumor vaccines have held much promise, but to date have demonstrated little clinical success. This lack of success is conceivably due to poor tumor antigen presentation combined with immuno-suppressive mechanisms exploited by the tumor itself. Knock down of Inhibitor of differentiation protein 2 (Id2-kd) in mouse neuroblastoma whole tumor cells rendered these cells immunogenic. Id2-kd neuroblastoma (Neuro2a) cells (Id2-kd N2a) failed to grow in most immune competent mice and these mice subsequently developed immunity against further wild-type Neuro2a tumor cell challenge. Id2-kd N2a cells grew aggressively in immune-compromised hosts, thereby establishing the immunogenicity of these cells. Therapeutic vaccination with Id2-kd N2a cells alone suppressed tumor growth even in established neuroblastoma tumors and when used in combination with immune checkpoint blockade eradicated large established tumors. Mechanistically, immune cell depletion studies demonstrated that while CD8+ T cells are critical for antitumor immunity, CD4+ T cells are also required to induce a sustained long-lasting helper effect. An increase in number of CD8+ T-cells and enhanced production of interferon gamma (IFNγ) was observed in tumor antigen stimulated splenocytes of vaccinated mice. More importantly, a massive influx of cytotoxic CD8+ T-cells infiltrated the shrinking tumor following combined immunotherapy. These findings show that down regulation of Id2 induced tumor cell immunity and in combination with checkpoint blockade produced a novel, potent, T-cell mediated tumor vaccine strategy.

No MeSH data available.


Related in: MedlinePlus