Enhancing the Systemic Anti-tumor Efficacy of [in-situ] Vaccines Against Advanced Tumors PDF Download

Author: Alexander Anthony Pieper
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Languages : en
Pages : 0

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Book Description
Despite advancements in our ability to diagnosis and treat cancer, cancer progression still occurs in many patients. Disease progression at sites other than the treated tumor remains an obstacle for improved patient outcomes. In-situ cancer vaccine strategies use immunotherapeutics to increase antigen processing and adaptive cell priming at one site of disease, and their objective is to have this adaptive response mediate tumor cell killing at the local, treated tumor and at distant, untreated sites of disease. The Sondel lab has developed an effective in-situ vaccine strategy that combines local external beam radiation therapy (RT) with intratumoral injections of immunocytokine, which is a fusion protein comprised of interleukin 2 (IL-2) attached to a monoclonal antibody. In the weakly immunogenic B78 melanoma model, this in-situ vaccine can cure mice of established tumors and generate an adaptive, tumor-specific memory response. If the B78 model is made more difficult to treat by adding a second untreated tumor to the model or allowing the tumors to grow larger in size before treatment, RT combined with immunocytokine demonstrates reduced anti-tumor efficacy. The goal of this thesis was to explore mechanisms to improve our in-situ vaccination strategies, with a particular emphasis geared towards improving the strength of in-situ vaccines under model conditions that are deemed "hard-to-treat." Research with a different in-situ vaccine, local injections of CpG oligodeoxynucleotide combined with an OX40 agonist antibody (CpG+OX40), has shown the combination synergizes to cure mice bearing multiple A20 lymphoma tumors. In these studies, however, the tumors were relatively small at the time treatment was initiated. Additionally, the A20 lymphoma model is considered relatively immunogenic. By evaluating the efficacy of this in-situ vaccine in both the B78 and A20 models, these studies demonstrate CpG+OX40 is an effective in-situ vaccination strategy against relatively small tumors. However, as tumor burden increases through the addition of a second untreated tumor or allowing tumors to grow larger before treatment is initiated, these studies show the efficacy of CpG+OX40 is reduced. In the A20 model, there are tumor phenotypic changes that develop in these larger tumors, which correlate with the reduced efficacy of this T cell dependent in-situ vaccine against larger tumors. Radiation therapy (RT) has been studied for its ability to turn a weakly immunogenic tumor into one that is more immunogenic. The Sondel and Morris labs have utilized these immune modulating capabilities in their research, demonstrating that local radiation can make a weakly immunogenic tumor more responsive to immunotherapy. Chapter 3 of this dissertation presents data demonstrating that local radiation prior to in-situ vaccination with CpG+OX40 can render a tumor, which was previously unlikely to respond to immunotherapy, more likely to shrink and go away. The data suggest RT is functioning to improve the anti-tumor response with CpG+OX40 by increasing antigen presentation and T cell activation. Though the in-situ vaccine regimen RT+CpG+OX40 can cure some mice of established B78 tumors, the cure rate of this regimen was reduced compared to the historical data of combining RT with immunocytokine. In an effort to improve the efficacy of our in-situ vaccine strategies, studies were performed investigating if RT could be combined with a different immunotherapeutic, a novel IL-2 receptor agonist Bempegaldesleukin, to activate a strong T cell mediated anti-tumor immune response. This combination, RT combined with Bempegaldesleukin, was capable of curing mice of B78 tumors that have historically been less responsive to RT combined with immunocytokine. Additionally, these studies demonstrated that addition of checkpoint blockade to this combination of RT with Bempegaldesleukin can further enhance the anti-tumor response in model conditions that more closely mimic the disease characteristics in patients. The preclinical laboratory development of this in-situ vaccine regimen, RT combined with Bempegaldesleukin and checkpoint blockade, contributed to the design and initiation of a clinical trial that is now opening to accrual.