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Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.
The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.
Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.
The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.
Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.
The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.
Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.
The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).
In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.
The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.
3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)
However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.
The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.
Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.
Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.
Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”
The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.
Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.
Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers. 
Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.
The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.
Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.
The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.
Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.
The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.
Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.
The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).
In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.
The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.
3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)
However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.
The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.
Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.
Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.
Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”
The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.
Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.
Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers.
Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.
The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.
Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.
The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.
Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.
The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.
Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.
The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).
In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.
The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.
3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)
However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.
The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.
Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.
Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.
Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”
The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.
Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.
Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers.