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Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer.

Cao ZA, Daniel D, Hanahan D - BMC Cancer (2002)

Bottom Line: In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival.In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival.Our data suggest that such resistance can be disrupted by sub-lethal radiation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, San Francisco, CA 94143-0534, USA. alex_cao001@hotmail.com

ABSTRACT

Background: It is not uncommon to observe circulating tumor antigen-specific T lymphocytes in cancer patients despite a lack of significant infiltration and destruction of their tumors. Thus, an important goal for tumor immunotherapy is to identify ways to modulate in vivo anti-tumor immunity to achieve clinical efficacy. We investigate this proposition in a spontaneous mouse tumor model, Rip1-Tag2.

Methods: Experimental therapies were carried out in two distinctive trial designs, intended to either intervene in the explosive growth of small tumors, or regress bulky end-stage tumors. Rip1-Tag2 mice received a single transfer of splenocytes from Tag-specific, CD4+ T cell receptor transgenic mice, a single sub-lethal radiation, or a combination therapy in which the lymphocyte transfer was preceded by the sub-lethal radiation. Tumor burden, the extent of lymphocyte infiltration into solid tumors and host survival were used to assess the efficacy of these therapeutic approaches.

Results: In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival. In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival.

Conclusions: The results indicate that certain types of solid tumors may be intrinsically resistant to infiltration and destruction by tumor-specific T lymphocytes. Our data suggest that such resistance can be disrupted by sub-lethal radiation. The combinatorial approach presented here merits consideration in the design of clinical trials aimed to achieve T cell-mediated anti-tumor immunity.

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Intervention trial. Effect of treatment on (A) the mean tumor volume (mm3) +/- standard deviation and (B) mean tumor number +/- standard deviation in 10 week old RIP1-Tag2 mice with small solid tumors for n = 8–11 mice. IT10w stands for initial tumor burden and tumor number. Statistical analysis was done using a two-tailed, unpaired Mann-Whitney test. P values comparing experimental groups to untreated control mice are 0.03 [1], 0.0004 [2], and 0.0044 [4], respectively. P value comparing 600R treated mice to TCR+600R is 0.0055 [3].
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Figure 1: Intervention trial. Effect of treatment on (A) the mean tumor volume (mm3) +/- standard deviation and (B) mean tumor number +/- standard deviation in 10 week old RIP1-Tag2 mice with small solid tumors for n = 8–11 mice. IT10w stands for initial tumor burden and tumor number. Statistical analysis was done using a two-tailed, unpaired Mann-Whitney test. P values comparing experimental groups to untreated control mice are 0.03 [1], 0.0004 [2], and 0.0044 [4], respectively. P value comparing 600R treated mice to TCR+600R is 0.0055 [3].

Mentions: We used two distinctive therapeutic trial designs for the treatment of tumors Rip1-Tag2 mice: intervention and regression [33]. In each trial we used three experimental arms as well as an untreated control group; the treatment arms were adoptive transfer of tumor antigen specific T cells, a sub-lethal dose of radiation (600R), or radiation followed by adoptive transfer. In the intervention trial, treatment occurred at a time when small, encapsulated adenomas are forming (week 10 for Rip1-Tag2 mice). The data are summarized in Figure 1. The mean tumor volume at the start of the trial was 3 mm3. The average number of tumors was 2.4. At the end of the study, the mean tumor burden in the untreated control group was about 34 mm3 in volume and 7.6 in tumor number. Adoptive transfer of splenocytes from TCR transgenic mice into Rip1-Tag2 mice produced a modest, but not statistically significant, reduction in tumor volume (35%), and no change in tumor number. Sub-lethal radiation alone significantly reduced tumor volume (53%, p = 0.03), but the mice had a similar number of tumors (6.4). With the combination treatment, a significant reduction in both tumor volume (87%; p = 0.0004) and tumor number was observed. It is notable that the mice receiving the combination treatment had a mean tumor volume of 4.6 mm3 (p = 0.0004) and an average tumor number of 2.3, comparable to the situation at the beginning of the trial. Thus, a condition of 'stable disease' was achieved in the group that received the combinatorial therapy


Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer.

Cao ZA, Daniel D, Hanahan D - BMC Cancer (2002)

Intervention trial. Effect of treatment on (A) the mean tumor volume (mm3) +/- standard deviation and (B) mean tumor number +/- standard deviation in 10 week old RIP1-Tag2 mice with small solid tumors for n = 8–11 mice. IT10w stands for initial tumor burden and tumor number. Statistical analysis was done using a two-tailed, unpaired Mann-Whitney test. P values comparing experimental groups to untreated control mice are 0.03 [1], 0.0004 [2], and 0.0044 [4], respectively. P value comparing 600R treated mice to TCR+600R is 0.0055 [3].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC113758&req=5

Figure 1: Intervention trial. Effect of treatment on (A) the mean tumor volume (mm3) +/- standard deviation and (B) mean tumor number +/- standard deviation in 10 week old RIP1-Tag2 mice with small solid tumors for n = 8–11 mice. IT10w stands for initial tumor burden and tumor number. Statistical analysis was done using a two-tailed, unpaired Mann-Whitney test. P values comparing experimental groups to untreated control mice are 0.03 [1], 0.0004 [2], and 0.0044 [4], respectively. P value comparing 600R treated mice to TCR+600R is 0.0055 [3].
Mentions: We used two distinctive therapeutic trial designs for the treatment of tumors Rip1-Tag2 mice: intervention and regression [33]. In each trial we used three experimental arms as well as an untreated control group; the treatment arms were adoptive transfer of tumor antigen specific T cells, a sub-lethal dose of radiation (600R), or radiation followed by adoptive transfer. In the intervention trial, treatment occurred at a time when small, encapsulated adenomas are forming (week 10 for Rip1-Tag2 mice). The data are summarized in Figure 1. The mean tumor volume at the start of the trial was 3 mm3. The average number of tumors was 2.4. At the end of the study, the mean tumor burden in the untreated control group was about 34 mm3 in volume and 7.6 in tumor number. Adoptive transfer of splenocytes from TCR transgenic mice into Rip1-Tag2 mice produced a modest, but not statistically significant, reduction in tumor volume (35%), and no change in tumor number. Sub-lethal radiation alone significantly reduced tumor volume (53%, p = 0.03), but the mice had a similar number of tumors (6.4). With the combination treatment, a significant reduction in both tumor volume (87%; p = 0.0004) and tumor number was observed. It is notable that the mice receiving the combination treatment had a mean tumor volume of 4.6 mm3 (p = 0.0004) and an average tumor number of 2.3, comparable to the situation at the beginning of the trial. Thus, a condition of 'stable disease' was achieved in the group that received the combinatorial therapy

Bottom Line: In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival.In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival.Our data suggest that such resistance can be disrupted by sub-lethal radiation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, San Francisco, CA 94143-0534, USA. alex_cao001@hotmail.com

ABSTRACT

Background: It is not uncommon to observe circulating tumor antigen-specific T lymphocytes in cancer patients despite a lack of significant infiltration and destruction of their tumors. Thus, an important goal for tumor immunotherapy is to identify ways to modulate in vivo anti-tumor immunity to achieve clinical efficacy. We investigate this proposition in a spontaneous mouse tumor model, Rip1-Tag2.

Methods: Experimental therapies were carried out in two distinctive trial designs, intended to either intervene in the explosive growth of small tumors, or regress bulky end-stage tumors. Rip1-Tag2 mice received a single transfer of splenocytes from Tag-specific, CD4+ T cell receptor transgenic mice, a single sub-lethal radiation, or a combination therapy in which the lymphocyte transfer was preceded by the sub-lethal radiation. Tumor burden, the extent of lymphocyte infiltration into solid tumors and host survival were used to assess the efficacy of these therapeutic approaches.

Results: In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival. In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival.

Conclusions: The results indicate that certain types of solid tumors may be intrinsically resistant to infiltration and destruction by tumor-specific T lymphocytes. Our data suggest that such resistance can be disrupted by sub-lethal radiation. The combinatorial approach presented here merits consideration in the design of clinical trials aimed to achieve T cell-mediated anti-tumor immunity.

Show MeSH
Related in: MedlinePlus