Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck.

BACKGROUND: The objective of this trial was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi-institutional, double-blind, randomized, placebo-controlled study format. METHODS: A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire. Weight, opiate use, and World Health Organization (WHO) oral mucositis (OM) scores were recorded. Subjects who dosed at least once daily during the first 2.5 weeks of CRT were included in the efficacy analysis. RESULTS: Of 120 subjects enrolled, 78 (SC, N=41; MuGard, N=37) were eligible for efficacy analysis. Both cohorts were similar in demographics, baseline characteristics, primary tumor type, and planned CRT regimen. MuGard effectively mitigated OM symptoms as reflected by area under the curve of daily patient-reported oral soreness (P=.034) and WHO scores on the last day of radiation therapy (P=.038). MuGard was also associated with nonsignificant trends related to therapeutic benefit including opioid use duration, and OM scores (WHO criteria) at CRT week 4. Rinse compliance was identical between cohorts. No significant adverse events were reported, and the adverse event incidence was similar between cohorts. CONCLUSIONS: Testing MuGard, a rinse marketed as a device, in a standard clinical trial format demonstrated its superiority to SC in mitigating OM symptoms, delaying OM progression, and its safety and tolerability.

The promise of combining radiation therapy and immunotherapy: morbidity and toxicity.

Radiation therapy and immunotherapy in partnership may have the capability of delivering a therapeutic effect exceeding the sum of its parts. The possible relationship has been demonstrated in murine models and has been extended to a variety of clinical trials. Though the standard notion of whole body radiation therapy is immunosuppressive, there is growing evidence toward the contrary for focal radiation therapy. Furthermore, if immunotherapeutic techniques can retune the immune system against cancerous cells, they should have obvious benefits for advanced treatments moving forward. Herein, we explore the promise in combining radiation therapy and immunotherapy with distinct focus on potential morbidities and toxicities through analysis of completed clinical trials.

Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer.

BACKGROUND: Sipuleucel-T is an autologous cellular immunotherapy approved by the US Food and Drug Administration for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Its mechanism of action is based on stimulation of the patient's own immune system to target prostate cancer. Peripheral blood mononuclear cells, including antigen-presenting cells and T cells, are obtained from patients via leukapheresis and treated ex vivo with PA2024, a fusion protein consisting of prostatic acid phosphatase/granulocyte-macrophage colony-stimulating factor antigen. METHODS: Data relating to the potential pharmacodynamic biomarkers associated with sipuleucel-T activity are reviewed, as well as considerations for patient selection and for sequencing sipuleucel-T with other prostate cancer treatments. Possible directions for future development are also discussed, including treatment of less advanced prostate cancer populations, combination treatment, and immune modulation. RESULTS: Data from three randomized, double-blind, placebo-controlled phase III clinical trials of sipuleucel-T in patients with metastatic castration-rresistant prostate cancer have shown improvement in overall survival vs control. Here, we review its developing role in prostate cancer therapy and future directions for development. CONCLUSIONS: There is potential to build on sipuleucel-T to further advance immunotherapy of prostate cancer.

Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function.

Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor gamma chain (gamma(c)), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-gamma production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R-/- mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.

Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells.

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The gammaC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of gammaC cytokine-responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

Improved survival in patients with lymph node-positive gastric cancer who received preoperative radiation: an analysis of the Surveillance, Epidemiology, and End Results database.

BACKGROUND: Several trials have been conducted to determine the feasibility of preoperative radiotherapy (RT) for gastric cancer. However, the absolute benefit from radiotherapy remains to be defined. In this study, the authors examined the use of preoperative RT (Pre-RT) and postoperative RT (PORT) in patients with gastric cancer from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The overall survival of patients who had nonmetastatic, resected gastric cancer between 2000 and 2006 was analyzed from the SEER database. Kaplan-Meier survival curves comparing Pre-RT, PORT, and no RT (No-RT) were analyzed using the log-rank test. A multivariate analysis (MVA) was conducted using Cox proportional hazards regression. RESULTS: The authors identified 10,251 patients. There was no survival benefit for patients who received Pre-RT or PORT compared with No-RT patients for the entire cohort. Conversely, among lymph node-positive patients, there was a significant survival benefit from both Pre-RT and PORT compared with No-RT (log-rank test: PORT, P < .0001; Pre-RT, P = .0261). The median survival and 5-year overall survival among lymph node-positive patients were 22 months and 24%, respectively, for Pre-RT;29 months and 34%, respectively, for PORT; and 19 months and 20%, respectively, for No-RT. MVA demonstrated that Pre-RT, PORT, and removing ≥ 15 lymph nodes were independent predictors of improved survival, whereas tumor classification, lymph node status, tumor size, and tumor location were independent predictors of death. CONCLUSIONS: The current results supported the use of Pre-RT in select patients with gastric cancer. However, additional trials will be needed to confirm these findings.

Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity.

Nonmutated tissue differentiation antigens expressed by tumors are attractive targets for cancer immunotherapy, but the consequences of a highly effective antitumor immune response on self-tissue have not been fully characterized. We found that the infusion of ex vivo expanded adoptively transferred melanoma/melanocyte-specific CD8+ T cells that mediated robust tumor killing also induced autoimmune destruction of melanocytes in the eye. This severe autoimmunity was associated with the up-regulation of MHC class I molecules in the eye and high levels of IFN-gamma derived from both adoptively transferred CD8+ T cells and host cells. Furthermore, ocular autoimmunity required the presence of the IFN-gamma receptor on target tissues. Data compiled from >200 eyes and tumors in 10 independently performed experiments revealed a highly significant correlation (P < 0.0001) between the efficacy of tumor immunotherapy and the severity of ocular autoimmunity. Administration of high doses of steroids locally mitigated ocular autoimmunity without impairing the antitumor effect. These findings have particular importance for immunotherapies directed against self-antigens and highlight the need for targeting unique tumor antigens not expressed in critical tissues.

Immune evasion by murine melanoma mediated through CC chemokine receptor-10.

Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)-dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression.

Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells.

Many tumor-associated antigens are derived from nonmutated "self" proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I-restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 mm2), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cyto-kine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.

Nonsurgical options for hepatocellular carcinoma: evolving role of external beam radiotherapy.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and thus poses a global concern. Its incidence is expected to increase in North America secondary to the increasing incidence of patients who develop hepatitis C. Patients who ultimately develop cirrhosis have an increased risk of developing hepatocellular carcinoma. METHODS: The authors focus on nonsurgical therapies for this disease with an exploration of how external beam radiotherapy can be used alone or with other modalities. The development of partial liver strategies secondary to an explosion in radiation treatment planning and delivery advances is reviewed. Integration of advanced technology has evolved from three-dimensional conformal treatment to intensity-modulated radiation therapy and image-guided radiation therapy, along with stereotactic body radiation therapy, tomotherapy, and proton beam therapy. RESULTS: Current data show a promising future for treatment strategies incorporating radiation with high rates of infield tumor control and low rates of radiation-induced liver disease. Radiation can be delivered in conjunction with transarterial catheter embolization for advanced-stage patients. External beam radiotherapy also has a role in the setting of patients with macrovascular tumor thrombus. CONCLUSIONS: Future directions include how to best synergize the effects of radiation strategies with novel agents, given the hypervascularity of HCC. Downstaging of larger lesions with these therapies to resectable or transplantable disease may lead to better outcomes for patients deemed inoperable at diagnosis, and definitive radiotherapy may offer cure to patients with smaller lesions.

Systemic therapy for advanced hepatocellular carcinoma: past, present, and future.

BACKGROUND: Although approximately 80% of hepatocellular carcinoma (HCC) cases occur in developing countries, the incidence of HCC in Western countries is on the rise due to the impact of hepatitis C. Challenges in developing effective therapies include the inherent chemoresistance of HCC, the pharmacologic challenges presented by a diseased liver, the presentation of most patients at advanced stages, and the difficulty in adequately measuring radiological response. While responses to traditional chemotherapeutic agents have been documented, significant survival benefit is debatable. METHODS: The authors review the results of published clinical trials of systemic therapy and immunotherapy that have impacted the present treatment of HCC. RESULTS: With recent progress in the elucidation of HCC molecular pathways, targeted agents show promise. The multikinase inhibitor sorafenib has provided survival benefit in patients with advanced HCC and well-preserved liver function. Sunitinib, bevacizumab, epidermal growth factor receptor inhibitors, and mammalian target of rapamycin (mTOR) inhibitors have shown activity in small patient cohorts. Immunotherapy appears to be a promising approach that can result in the regression of bulky, invasive cancer in some patients. CONCLUSIONS: New agents with a variety of mechanisms of activity offer promising therapeutic options for patients with advanced HCC.

Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.

T cell differentiation is a progressive process characterized by phenotypic and functional changes. By transferring tumor-specific CD8+ T cells into tumor-bearing mice at various stages of differentiation, we evaluated their efficacy for adoptive immunotherapy. We found that administration of naive and early effector T cells, in combination with active immunization and IL-2, resulted in the eradication of large, established tumors. Despite enhanced in vitro antitumor properties, more-differentiated effector T cells were less effective for in vivo tumor treatment. Several events may underlie this paradoxical phenomenon: (a) downregulation of lymphoid-homing and costimulatory molecules; (b) inability to produce IL-2 and access homeostatic cytokines; and (c) entry into a proapoptotic and replicative senescent state. While the progressive acquisition of terminal effector properties is characterized by pronounced in vitro tumor killing, in vivo T cell activation, proliferation, and survival are progressively impaired. These findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.

Combined [18F]Fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) for detection of recurrent, 131I-negative thyroid cancer.

BACKGROUND: Whole-body (131)I scintigraphy (WBS) and serial thyroglobulin measurement (Tg) are standard methods for detecting thyroid cancer recurrence after total/near total thyroidectomy and (131)I ablation. Some patients develop elevated Tg (Tg-positive) or there is clinical suspicion of recurrence, but WBS are negative (WBS-negative). This may reflect non-iodine-avid recurrence or metastasis. In 2002, the Centers for Medicare and Medicaid Services (CMS) approved positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) for Tg-positive/WBS-negative patients with follicular-cell-origin thyroid cancer. Limited data are available regarding the performance of combined FDG-PET/computed tomography (FDG-PET/CT) for detecting recurrent thyroid cancer in WBS-neg patients. METHODS: This retrospective review of prospectively collected data analyzed 65 patients who had FDG-PET/CT for suspected thyroid cancer recurrence (April 1998-August 2006). Patients were WBS-negative but were suspected to have recurrence based on Tg levels or clinical grounds. Suspected FDG-PET/CT abnormalities were reported as benign or malignant. Lesions were ultimately declared benign or malignant by surgical pathology or clinical outcome (disease progression). RESULTS: Of 65 patients who underwent FDG-PET/CT, 47 had positive FDG-PET/CT. Of the positive FDG-PET/CT, 43 studies were true positives, with 21 (49%) confirmed pathologically by surgical resection. The four false positives (3/4 confirmed pathologically) included an infundibular cyst, an inflamed supraclavicular cyst, pneumonitis, and degenerative disc disease. Of the 18 FDG-PET/CT studies that were negative, 17 were true negatives and one was a false negative (metastatic papillary carcinoma). Thus, FDG-PET/CT demonstrated a patient-based sensitivity of 98%, specificity of 81%, positive predictive value of 91%, and negative predictive value of 94%. CONCLUSIONS: FDG-PET/CT is useful for detecting thyroid cancer recurrence in WBS-negative patients, and can assist decision making.

Radiation dose and cardiac risk in breast cancer treatment: An analysis of modern radiation therapy including community settings.

PURPOSE: Adjuvant radiation therapy (RT) for breast cancer improves outcomes, but prior studies have documented substantive cardiac dose and cardiac risk. We assessed the mean heart dose (MHD) of RT and estimated the risk of RT-associated cardiac toxicity in women undergoing adjuvant RT for breast cancer in contemporary (predominantly) community practice. METHODS AND MATERIALS: We identified women with left-sided breast cancer receiving adjuvant RT between 2012 and 2014 from 94 centers across 16 states. We used bivariate analyses and multivariable linear regression to assess associations between RT techniques and MHD. Excess RT-related cardiac risk by age 80 was estimated for women diagnosed at age 60 using the previously reported relationship between MHD and cardiac risk. RESULTS: Among 1161 women, 77.3% were treated in community practice and with breast conservation (77.8%). The most common techniques were free-breathing (92.2%), supine (94.8%), and fixed gantry intensity modulated RT (FG-IMRT; 46.9%). The median MHD was 2.76 Gy (interquartile range, 1.47-5.03). In multivariable analyses, the predicted median MHD with deep inspiration breath hold was 2.41 Gy compared with 3.86 Gy with free-breathing (P < .001). Three-dimensional conformal RT (3D-CRT) was associated with a lower predicted median MHD (2.78 Gy) than FG-IMRT (4.02 Gy) or rotational IMRT, 6.60 Gy, P < .001). For 60-year-old women with the median MHD of the study population (2.76 Gy) and no cardiovascular risk factors, the 20-year predicted excess risk of death from ischemic heart disease attributable to radiation was 3.5 excess events/1000 patients, in contrast to estimates of 8 events/1000 from prior analyses. The predicted risk of cardiac events varied based on radiation technique, with 4 excess events/1000 with 3D-CRT, 5 excess events/1000 with FG-IMRT, and 8 excess events/1000 with rotational IMRT. CONCLUSIONS: MHD varies substantially across patients and is influenced by technique in predominantly community settings. Overall risk of cardiac toxicity is modest.

Report from the SWOG Radiation Oncology Committee: Research Objectives Workshop 2017.

The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology-specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500-9. ©2018 AACR.

Bcl-2 overexpression enhances tumor-specific T-cell survival.

Although immunotherapy based on the adoptive transfer of tumor-specific T lymphocytes has been shown to result in dramatic clinical responses in some patients, the relatively low levels of engraftment and persistence of the adoptively transferred cells may limit these responses in many patients. In an attempt to develop strategies for prolonging the survival of adoptively transferred T cells, we have carried out studies in which T cells obtained from healthy donors as well as tumor-specific T cells were transduced with a retrovirus expressing the human Bcl-2 gene. Our results indicate that these transduced T cells overexpress Bcl-2, are resistant to death, and have a survival advantage following interleukin-2 withdrawal compared with control T cells transduced with a retrovirus expressing green fluorescent protein. Tumor-specific T cells overexpressing Bcl-2 maintained their ability to specifically recognize and respond to target cells. Furthermore, we show that adoptive immunotherapy of an established B16 tumor can be significantly enhanced by overexpressing Bcl-2 in melanoma-specific T-cell receptor transgenic T cells. Our data suggest that adoptive immunotherapy approaches to the treatment of cancer patients may be enhanced using Bcl-2-modified tumor-reactive T cells.

The Role of Therapeutic Layering in Optimizing Treatment for Patients With Castration-resistant Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II).

OBJECTIVE: To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific castration-resistant prostate cancer (CRPC) treatments. MATERIALS AND METHODS: The Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for metastatic CRPC based on available data and clinical experience. RESULTS: A consensus was developed to address important questions on management of patients with metastatic CRPC. CONCLUSION: In the absence of large-scale clinical trials, the Working Group recommends that patients may best be managed with a layered approach of approved therapies with unique or complimentary mechanisms of action.

Dendritic cells strongly boost the antitumor activity of adoptively transferred T cells in vivo.

Dendritic cells (DCs) have been well characterized for their ability to initiate cell-mediated immune responses by stimulating naive T cells. However, the use of DCs to stimulate antigen-activated T cells in vivo has not been investigated. In this study, we determined whether DC vaccination could improve the efficacy of activated, adoptively transferred T cells to induce an enhanced antitumor immune response. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without concurrent peptide-pulsed DC vaccination. In this model, antigen-specific DC vaccination induced cytokine production, enhanced proliferation, and increased tumor infiltration of adoptively transferred T cells. Furthermore, the combination of DC vaccination and adoptive T-cell transfer led to a more robust antitumor response than the use of each treatment individually. Collectively, these findings illuminate a new potential application for DCs in the in vivo stimulation of adoptively transferred T cells and may be a useful approach for the immunotherapy of cancer.

Abscopal Benefits of Localized Radiotherapy Depend on Activated T-cell Trafficking and Distribution between Metastatic Lesions.

It remains unclear how localized radiotherapy for cancer metastases can occasionally elicit a systemic antitumor effect, known as the abscopal effect, but historically, it has been speculated to reflect the generation of a host immunotherapeutic response. The ability to purposefully and reliably induce abscopal effects in metastatic tumors could meet many unmet clinical needs. Here, we describe a mathematical model that incorporates physiologic information about T-cell trafficking to estimate the distribution of focal therapy-activated T cells between metastatic lesions. We integrated a dynamic model of tumor-immune interactions with systemic T-cell trafficking patterns to simulate the development of metastases. In virtual case studies, we found that the dissemination of activated T cells among multiple metastatic sites is complex and not intuitively predictable. Furthermore, we show that not all metastatic sites participate in systemic immune surveillance equally, and therefore the success in triggering the abscopal effect depends, at least in part, on which metastatic site is selected for localized therapy. Moreover, simulations revealed that seeding new metastatic sites may accelerate the growth of the primary tumor, because T-cell responses are partially diverted to the developing metastases, but the removal of the primary tumor can also favor the rapid growth of preexisting metastatic lesions. Collectively, our work provides the framework to prospectively identify anatomically defined focal therapy targets that are most likely to trigger an immune-mediated abscopal response and therefore may inform personalized treatment strategies in patients with metastatic disease.