Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[C-11]Methyl-AMD3465 PET

Purpose Chemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[C-11]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization. Procedure TC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[C-11]methyl-AMD3465 PET. Results PET imaging showed N-[C-11]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 +/- 0.31 %ID/g vs. 0.42 +/- 0.05 % ID/g, p <0.01). The tumor uptake was further increased by 4-fold (1.73 +/- 0.17 % ID/g vs 0.42 +/- 0.05 % ID/g, p <0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 +/- 0.1 % ID/g, p <0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis. Conclusion This study demonstrates the feasibility of N-[C-11]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies

Strategies to Target Tumor Immunosuppression

The tumor microenvironment is currently in the spotlight of cancer immunology research as a key factor impacting tumor development and progression. While antigen-specific immune responses play a crucial role in tumor rejection, the tumor hampers these immune responses by creating an immunosuppressive microenvironment. Recently, major progress has been achieved in the field of cancer immunotherapy, and several groundbreaking clinical trials demonstrated the potency of such therapeutic interventions in patients. Yet, the responses greatly vary among individuals. This calls for the rational design of more efficacious cancer immunotherapeutic interventions that take into consideration the “immune signature” of the tumor. Multimodality treatment regimens that aim to enhance intratumoral homing and activation of antigen-specific immune effector cells, while simultaneously targeting tumor immunosuppression, are pivotal for potent antitumor immunity

Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[C-11]Methyl-AMD3465 PET

Purpose Chemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[C-11]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization. Procedure TC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[C-11]methyl-AMD3465 PET. Results PET imaging showed N-[C-11]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 +/- 0.31 %ID/g vs. 0.42 +/- 0.05 % ID/g, p &lt;0.01). The tumor uptake was further increased by 4-fold (1.73 +/- 0.17 % ID/g vs 0.42 +/- 0.05 % ID/g, p &lt;0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 +/- 0.1 % ID/g, p &lt;0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis. Conclusion This study demonstrates the feasibility of N-[C-11]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies.</p

Noninvasive monitoring of cancer therapy induced activated T cells using [F-18]FB-IL-2 PET imaging

Cancer immunotherapy urgently calls for methods to monitor immune responses at the site of the cancer. Since activated T lymphocytes may serve as a hallmark for anticancer responses, we targeted these cells using the radiotracer N-(4-[F-18] fluorobenzoyl)-interleukin-2 ([F-18] FB-IL-2) for positron emission tomography (PET) imaging. Thus, we noninvasively monitored the effects of local tumor irradiation and/or immunization on tumor-infiltrating and systemic activated lymphocytes in tumor-bearing mice. A 10- and 27-fold higher [F-18] FB-IL-2 uptake was observed in tumors of mice receiving tumor irradiation alone or in combination with immunization, respectively. This increased uptake was extended to several non-target tissues. Administration of the CXCR4 antagonist AMD3100 reduced tracer uptake by 2.8-fold, indicating a CXCR4-dependent infiltration of activated T lymphocytes upon cancer treatment. In conclusion, [F-18] FB-IL-2 PET can serve as a clinical biomarker to monitor treatment-induced infiltration of activated T lymphocytes and, on that basis, may guide cancer immunotherapies