Adoptive cell therapy using gene-modified T-cells has achieved impressive results in the treatment of B-cell malignancies. However, the development of similar strategies to treat solid tumors raises challenges with respect to tumor antigen selection and the achievement of efficient T-cell homing, survival and sustained effector function within the tumor microenvironment. To address these challenges, we have developed a gene-modified cellular therapy called T4 immunotherapy. To generate T4 immunotherapy, autologous T-cells are engineered by retroviral transduction to co-express two transgenes: (1) a chimeric antigen receptor (CAR), T1E28z, targeted against a range of ErbB homodimers and heterodimers and (2) a chimeric cytokine receptor, 4αβ, that allows the selective ex vivo expansion of engineered cells using interleukin-4. Targeting of the extended ErbB network using CAR T-cells is supported by prevalence of ErbB dysregulation in diverse solid tumors and the clinical impact of monoclonal antibody therapy directed against members of this family. However, the key obstacle to effective clinical translation is risk of on-target toxicity owing to the lower level expression of ErbB family members in many healthy tissues. To de-risk T4 immunotherapy in man, we are undertaking a trial in patients with locally advanced or recurrent head and neck squamous cell carcinoma. In that setting, engineered T-cells are injected directly into the tumor without prior lymphodepletion, an approach that we believe will minimize risk of toxicity. This chapter outlines how we plan to advance the development of T4 immunotherapy thereafter in Phase II clinical testing. In that setting, regional (intracavitary) approaches will be used to administer this therapy to patients with epithelial ovarian cancer and malignant pleural mesothelioma.