While anti-CEA antibodies have no direct effect on CEA-positive tumors, they can be used to direct potent antitumor effects as an antibody-IL-2 fusion protein (immunocytokine, ICK), and at the same time reduce the toxicity of IL-2 as a single agent. Using a fusion protein of humanized anti-CEA with human IL-2 (M5A-IL-2) in a transgenic murine model expressing human CEA, we show high tumor uptake of the ICK to CEA-positive tumors with additional lymph node targeting. ICK treated CEA-positive tumors exhibit significant tumor eradication. Analysis of tumor-infiltrating lymphocytes shows a high frequency of both CD8 + and CD4 + T cells along with CD11b positive myeloid cells in ICK treated mice. The frequency of tumor-infiltrating FoxP3 + CD4 + T cells (Tregs) is significantly reduced vs anti-CEA antibody-treated controls, indicating that ICK did not preferentially stimulate migration or proliferation of Tregs to the tumor. Combination therapy with anti-PD-1 antibody did not improve tumor reduction over ICK therapy alone. Since stereotactic tumor irradiation (SRT), commonly used in cancer therapy has immunomodulatory effects, we tested combination SRT+ICK therapy in two tumor model systems. Use of fractionated vs single high dose SRT in combination with ICK resulted in greater tumor inhibition and immunity to tumor rechallenge. In particular, tumor microenvironment and myeloid cell composition appear to play a significant role in the response rate to ICK+SRT combination therapy.

Patients with refractory leukemia or minimal residual disease (MRD) at transplant have increased risk of relapse. Augmentation of irradiation, especially to sites of disease (i.e., bone marrow) is one potential strategy to overcome this risk. We studied the feasibility of radiation dose escalation in high risk patients using total marrow irradiation (TMI) in a phase I dose-escalation trial. Four pediatric and 8 adult patients received conditioning with cyclophosphamide and fludarabine in conjunction with image-guided radiation to the bone marrow at 15 Gy and 18 Gy (in 3 Gy/fractions), while maintaining the total body irradiation (TBI) dose to the vital organs (lungs, hearts, eyes, liver, kidneys) at <13.2 Gy. The biologically effective dose (BED) of TMI delivered to the bone marrow was increased by 62% and 96% at 15 and 18 Gy compared to standard TBI. While excessive dose-limiting toxicity defined by graft failure or excess specific organ toxicity was not encountered, three of six patients experienced treatment-related mortality (TRM) at 18Gy. Thus, we halted enrollment at this dose level and treated an additional 4 patients at 15 Gy. The 1 year OS was 42% (CI 95%, 15–67%) and DFS was 22% (CI 95%, 4–49%). The rate of relapse was 36% (CI 95%, 10–62%) and the non-relapse mortality was 42% (CI 95%, 14–70%). This study shows that dose escalation of TMI to 15 Gy is feasible with acceptable toxicity in pediatric and adult high risk leukemia patients undergoing umbilical cord blood (UCB) and sibling donor transplantation.

Prostate cancer is one of the most commonly diagnosed cancers and a pressing health challenge in men worldwide. Radiation therapy (RT) is widely considered a standard therapy for advanced as well as localized prostate cancer. Although this primary therapy is associated with high cancer control rates, up to one‐third of patients undergoing radiation therapy becomes radio‐resistant and/or has tumor‐relapse/recurrence. Therefore, focus on new molecular targets and pathways is essential to develop novel radio‐sensitizing agents for the effective and safe treatment of prostate cancer. Here, we describe functional studies that were performed to investigate the role of structural maintenance of chromosome‐1 (SMC1A) in radioresistance of metastatic prostate cancer cells. Short hairpin RNA (shRNA) was used to suppress SMC1A in metastatic castration‐resistant prostate cancer cells, DU145 and PC3. Clonogenic survival assays, Western blot, RT‐PCR, and γ‐H2AX staining were used to assess the effect of SMC1A knockdown on radiation sensitivity of these prostate cancer cells. We demonstrate that SMC1A is overexpressed in human prostate tumors compared to the normal adjacent tissue. SMC1A knockdown limits the clonogenic potential, epithelial‐mesenchymal transition (EMT), and cancer stem‐like cell (CSC) properties of DU145 and PC3 cells and enhanced efficacy of RT in these cells. Targeted inhibition of SMC1A not only plays a critical role in overcoming radio‐resistance in prostate cancer cells, but also suppresses self‐renewal and the tumor‐propagating potential of x‐irradiated cancer cells. We propose that SMC1A could be a potential molecular target for the development of novel radio‐sensitizing therapeutic agents for management of radio‐resistant metastatic prostate cancer.

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