Limits...
Adoptive T-cell therapy improves treatment of canine non-Hodgkin lymphoma post chemotherapy.

O'Connor CM, Sheppard S, Hartline CA, Huls H, Johnson M, Palla SL, Maiti S, Ma W, Davis RE, Craig S, Lee DA, Champlin R, Wilson H, Cooper LJ - Sci Rep (2012)

Bottom Line: Graded doses of autologous T cells were infused after CHOP chemotherapy and persisted for 49 days, homed to tumor, and significantly improved survival.Serum thymidine kinase changes predicted T-cell engraftment, while anti-tumor effects correlated with neutrophil-to-lymphocyte ratios and granzyme B expression in manufactured T cells.The companion canine model has translational implications for human immunotherapy which can be readily exploited since clinical-grade canine and human T cells are propagated using identical approaches.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

ABSTRACT
Clinical observations reveal that an augmented pace of T-cell recovery after chemotherapy correlates with improved tumor-free survival, suggesting the add-back of T cells after chemotherapy may improve outcomes. To evaluate adoptive immunotherapy treatment for B-lineage non-Hodgkin lymphoma (NHL), we expanded T cells from client-owned canines diagnosed with NHL on artificial antigen presenting cells (aAPC) in the presence of human interleukin (IL)-2 and IL-21. Graded doses of autologous T cells were infused after CHOP chemotherapy and persisted for 49 days, homed to tumor, and significantly improved survival. Serum thymidine kinase changes predicted T-cell engraftment, while anti-tumor effects correlated with neutrophil-to-lymphocyte ratios and granzyme B expression in manufactured T cells. Therefore, chemotherapy can be used to modulate infused T-cell responses to enhance anti-tumor effects. The companion canine model has translational implications for human immunotherapy which can be readily exploited since clinical-grade canine and human T cells are propagated using identical approaches.

Show MeSH

Related in: MedlinePlus

Adoptive transfer of ex vivo propagated T cells after CHOP improves survival of canines with NHL.Differences between 12 historical stage-, age-, and size-matched controls treated with CHOP (red dashed line) and 7 (curve A) or 8 (curve B) research participants treated with CHOP and T cells (blue solid line) over 500 days in evaluating (a) tumor-free survival measured after achieving CR (p = 0.005) and (b) overall survival measured upon diagnosis of NHL diagnosis (p = 0.03). One dog (P42) had progressive disease at the time of T-cell infusions and was not evaluated in the tumor-free survival analysis, but was included in the overall survival analysis. This patient had stable disease for 112 days after study day 14.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3278154&req=5

f5: Adoptive transfer of ex vivo propagated T cells after CHOP improves survival of canines with NHL.Differences between 12 historical stage-, age-, and size-matched controls treated with CHOP (red dashed line) and 7 (curve A) or 8 (curve B) research participants treated with CHOP and T cells (blue solid line) over 500 days in evaluating (a) tumor-free survival measured after achieving CR (p = 0.005) and (b) overall survival measured upon diagnosis of NHL diagnosis (p = 0.03). One dog (P42) had progressive disease at the time of T-cell infusions and was not evaluated in the tumor-free survival analysis, but was included in the overall survival analysis. This patient had stable disease for 112 days after study day 14.

Mentions: To evaluate the ability of ex vivo-propagated T cells to impact canine survival, we compared the 8 dogs that received CHOP and autologous T cells with a cohort of stage-matched canines with NHL that received only CHOP. Both cohorts were followed for 500 days post initial diagnosis of NHL or obtaining CR for the analysis of tumor-free survival. As expected, 7 of 8 dogs that received T-cell infusions achieved a prior complete remission (CR) from CHOP. However, we observed that the infusion of T cells after CHOP resulted in marked improvements in overall and tumor-free survival and that this was evident when only 8 dogs had been infused (Fig 5). The historical controls which were matched for age, size, disease stage, and achieving CR after CHOP with the canines that received T cells after CHOP. This control population had a median overall survival (n = 12) of 167 days (range from 68 to 413 days) upon initial diagnosis of NHL and a median tumor-free survival (n = 12) of 71 days (range from 23 to 293 days) following the CR achieved after receiving CHOP. Significantly, for the 8 canines receiving CHOP combined with T-cell infusions the median overall survival was improved to 392 days (range 277 to 458 days) and the tumor-free survival improved to 338 days (range 104 to 369 days). The hazard ratio and p-value for the log rank test of overall survival were 4.3 and 0.03, respectively. T-cell infusions significantly increased the period of tumor-free survival when used in conjunction with CHOP therapy (p = 0.005) which implies a clinical benefit to dogs with NHL that received immunotherapy.


Adoptive T-cell therapy improves treatment of canine non-Hodgkin lymphoma post chemotherapy.

O'Connor CM, Sheppard S, Hartline CA, Huls H, Johnson M, Palla SL, Maiti S, Ma W, Davis RE, Craig S, Lee DA, Champlin R, Wilson H, Cooper LJ - Sci Rep (2012)

Adoptive transfer of ex vivo propagated T cells after CHOP improves survival of canines with NHL.Differences between 12 historical stage-, age-, and size-matched controls treated with CHOP (red dashed line) and 7 (curve A) or 8 (curve B) research participants treated with CHOP and T cells (blue solid line) over 500 days in evaluating (a) tumor-free survival measured after achieving CR (p = 0.005) and (b) overall survival measured upon diagnosis of NHL diagnosis (p = 0.03). One dog (P42) had progressive disease at the time of T-cell infusions and was not evaluated in the tumor-free survival analysis, but was included in the overall survival analysis. This patient had stable disease for 112 days after study day 14.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3278154&req=5

f5: Adoptive transfer of ex vivo propagated T cells after CHOP improves survival of canines with NHL.Differences between 12 historical stage-, age-, and size-matched controls treated with CHOP (red dashed line) and 7 (curve A) or 8 (curve B) research participants treated with CHOP and T cells (blue solid line) over 500 days in evaluating (a) tumor-free survival measured after achieving CR (p = 0.005) and (b) overall survival measured upon diagnosis of NHL diagnosis (p = 0.03). One dog (P42) had progressive disease at the time of T-cell infusions and was not evaluated in the tumor-free survival analysis, but was included in the overall survival analysis. This patient had stable disease for 112 days after study day 14.
Mentions: To evaluate the ability of ex vivo-propagated T cells to impact canine survival, we compared the 8 dogs that received CHOP and autologous T cells with a cohort of stage-matched canines with NHL that received only CHOP. Both cohorts were followed for 500 days post initial diagnosis of NHL or obtaining CR for the analysis of tumor-free survival. As expected, 7 of 8 dogs that received T-cell infusions achieved a prior complete remission (CR) from CHOP. However, we observed that the infusion of T cells after CHOP resulted in marked improvements in overall and tumor-free survival and that this was evident when only 8 dogs had been infused (Fig 5). The historical controls which were matched for age, size, disease stage, and achieving CR after CHOP with the canines that received T cells after CHOP. This control population had a median overall survival (n = 12) of 167 days (range from 68 to 413 days) upon initial diagnosis of NHL and a median tumor-free survival (n = 12) of 71 days (range from 23 to 293 days) following the CR achieved after receiving CHOP. Significantly, for the 8 canines receiving CHOP combined with T-cell infusions the median overall survival was improved to 392 days (range 277 to 458 days) and the tumor-free survival improved to 338 days (range 104 to 369 days). The hazard ratio and p-value for the log rank test of overall survival were 4.3 and 0.03, respectively. T-cell infusions significantly increased the period of tumor-free survival when used in conjunction with CHOP therapy (p = 0.005) which implies a clinical benefit to dogs with NHL that received immunotherapy.

Bottom Line: Graded doses of autologous T cells were infused after CHOP chemotherapy and persisted for 49 days, homed to tumor, and significantly improved survival.Serum thymidine kinase changes predicted T-cell engraftment, while anti-tumor effects correlated with neutrophil-to-lymphocyte ratios and granzyme B expression in manufactured T cells.The companion canine model has translational implications for human immunotherapy which can be readily exploited since clinical-grade canine and human T cells are propagated using identical approaches.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

ABSTRACT
Clinical observations reveal that an augmented pace of T-cell recovery after chemotherapy correlates with improved tumor-free survival, suggesting the add-back of T cells after chemotherapy may improve outcomes. To evaluate adoptive immunotherapy treatment for B-lineage non-Hodgkin lymphoma (NHL), we expanded T cells from client-owned canines diagnosed with NHL on artificial antigen presenting cells (aAPC) in the presence of human interleukin (IL)-2 and IL-21. Graded doses of autologous T cells were infused after CHOP chemotherapy and persisted for 49 days, homed to tumor, and significantly improved survival. Serum thymidine kinase changes predicted T-cell engraftment, while anti-tumor effects correlated with neutrophil-to-lymphocyte ratios and granzyme B expression in manufactured T cells. Therefore, chemotherapy can be used to modulate infused T-cell responses to enhance anti-tumor effects. The companion canine model has translational implications for human immunotherapy which can be readily exploited since clinical-grade canine and human T cells are propagated using identical approaches.

Show MeSH
Related in: MedlinePlus