- PROJECT 3: We are developing a combination of immunotherapy (ImmRx) and radiotherapy (RT) that shows potent synergy in eradicating cancer in mice with multiple sites of immunologically ?cold? tumors, which have few infiltrating T cells and do not respond to immune checkpoint inhibition (ICI). Virtually all pediatric cancers and most cancers of adults are cold, with few mutations or neoantigens. We are now taking a systematic approach to enable potent immune-induced eradication of most cold tumors aimed towards clinical translation. We have eradicated large, cold tumors in mice by combining immunomodulatory (12 Gy) external beam RT (EBRT) with intratumoral (IT) injection of tumor-specific antibody (mAb) + IL2. This approach induces T-cell infiltration into these tumors, potent T-cell memory, epitope spread, and protection from tumor re-challenge. However, the presence of an identical but untreated second tumor (2) on a mouse?s opposite flank inhibits the effect of this treatment, preventing eradication of the primary (1) tumor treated with EBRT + IT mAb-IL2. In this setting, the untreated 2 tumor causes tumor-specific immune unresponsiveness to EBRT + IT mAb-IL2 at the 1 tumor. We refer to this as concomitant immune tolerance (CIT). We can overcome CIT and eliminate both tumors by giving IT mAb-IL2 to the 1 tumor and EBRT to both the 1 and 2 tumors. Delivering as little as 2-5 Gy RT to the 2 tumor can overcome CIT. However, the provision of systemic EBRT to treat many sites of metastases is problematic, due to systemic immune suppression from EBRT; but this can effectively be achieved without immune-suppression using molecular targeted radionuclide therapy (TRT). 131I-MIBG is a common TRT for neuroblastoma (NBL). Our University of Wisconsin P01 team has led preclinical/clinical testing of a novel TRT using alkyl-phospho-choline (APCh) analogs that selectively deliver radionuclides to cancers in vivo. These show >10-fold uptake over 131I-MIBG in NBL xenografts, but unlike MIBG, show similar uptake in NBL and virtually all tumors tested. Our lead-candidate form of TRT, 90Y-NM600 has many conceptual and clinical advantages over 131I-MIBG, including potential outpatient treatment with no need for patient isolation. We have demonstrated potent synergy with 90Y-NM600 and ImmRx in our mouse models. This project expands the ongoing collaborative progress of the several collaborative projects and cores in this P01 proposal to systematically develop the potency of combining TRT with our combination ImmRx. We will pursue this synergy in immunocompetent mouse models of cold NBL and sarcomas. Our in vivo goal is the ability to use TRT to help eradicate all cancer in mice bearing macroscopic tumors in two separate sites as well as disseminated micro-metastases. We will carefully analyze tumor and immune parameters at the histological, cellular, and molecular levels in treated and control mice and in mice that are cured vs. mice that show progression or relapse. In addition, we will integrate into our testing novel new vectors for delivering TRT. The insights/regimens developed here should enable rapid translation to cold clinical cancers.
? PROJECT 3 We are developing a new approach, representing a dramatic shift in the treatment of high-risk pediatric and adult cancers. Our strategy utilizes immune responses to recognize and destroy cancer (immunotherapy) in combination with low-dose radiation therapy, which substantially improves the anti-tumor potency of the immunotherapy regimens we are creating. In our novel approach, we will administer a low-dose, targeted radionuclide that can be injected into a vein and preferentially deliver molecular radiotherapy to primary, local, and distant tumors throughout the body. We will combine this with immunotherapy approaches in mouse models of different childhood cancers to determine which combinations may lead to the most beneficial strategies to cure high-risk pediatric and adult cancers in humans and advance the National Cancer Institute?s mission to help people live longer, healthier lives.