Metastatic cancer has historically been considered incurable. Recent advances in immunotherapy have led to improved long-term complete responses, but only a subset of these patient see benefit. An additional proportion of patients with metastatic disease may experience systemic effects from local therapies such as stereotactic ablative radiotherapy (SABR). First described by R.H. Mole, the abscopal effect refers to an immune-mediated response of distant lesions to irradiation of other lesions; Mole considered this evidence that radiation turned lesions into “in situ vaccines” [1]. However, abscopal effects are quite rare in clinical practice [2], and factors that may amplify the occurrence of this phenomenon remain elusive.

Preclinical studies have suggested that low-dose radiation, although not tumoricidal on its own, may activate and stimulate immune cells and modulate the stromal microenvironment so as to facilitate the action of immunotherapy [3]. Our own post-hoc analysis of a recently completed trial of ipilimumab with high-dose radiation revealed that tumors exposed to low-dose scatter radiation (owing to their proximity to the targeted tumor) were more likely to show a response than were distant tumors exposed to no radiation [4]. From these observations, we developed a model where high-dose and low-dose radiation may work synergistically to promote systemic immunotherapy: In this model, high-dose radiation increases antigen release and presentation and primes immune cells [5], whereas low-dose radiation promotes immune-cell infiltration into the stroma and tumor bed.

Here we report on a subset of 26 patients from ongoing prospective trials of immunotherapy with radiation for metastatic cancer to further expand on our previous post-hoc analysis. These patients received low-dose radiation to metastatic lesions in combination with high-dose SABR to another lesion along with checkpoint inhibitors. We report outcomes in terms of the response of those low-dose–irradiated lesions, as well as responses of unirradiated lesions, in these patients. Our results suggest that low-dose radiation may be capable of enhancing an immune response that leads to abscopal effects.

This post hoc analysis was reviewed and approved by the UT MDACC institutional review board. We retrospectively reviewed electronic medical records and radiation treatment plans from 155 patients enrolled and treated on our three institutional prospective clinical trials combining immunotherapy and radiation: a phase I/II “basket” trial of ipilimumab (anti-CTLA4) with SABR for patients with liver or lung metastases (NCT02239900), a phase I/II randomized trial of pembrolizumab (anti-PD1) with SABR for patients with non-small cell lung cancer (NCT02444741), and phase II “basket” trial of SABR + low-dose radiation for patients with disease progression on immunotherapy (NCT02710253); treatment took place from August 2013 through March 2019. From the datasets and radiation treatment plans of all three prospective studies, we identified 26 patients who had lesions that received low-dose radiation (“low-dose” lesions), i.e., doses of 1–20 Gy, either intentionally or unintentionally; 22 of these patients also had lesions that received < 1 Gy (“no-dose” lesions). We compared rates and extent of response of the low-dose and no-dose lesions as follows.

Lesion diameters were measured on computed tomography (CT) or positron emission tomography (PET) /CT scans of the chest, abdomen, and pelvis, and the longest diameter of each lesion were used to assess changes in lesion size. Lesion response was accessed using RECIST criteria for response, using the largest diameter of each lesion [6]. Briefly, a complete response (CR) is defined as 100% resolution of the lesion, partial response (PR) as a reduction of ≥30%, stable disease (SD) as a reduction of < 30% to an increase of < 20%, and progressive disease (PD) as an increase of > 20% in lesion size. Response was to be assessed every 3 months per specific protocol, with the same imaging modality to be used before and after treatment.

Lesions were contoured on the original treatment plan, and information on radiation doses including mean doses for each individual lesion were collected from dose-volume histograms from radiation treatment plans that had been created on a Philips Pinnacle³ radiation treatment planning system with the help of the study dosimetrist. All lesions and doses were approved by the treating radiation oncologist.

Twenty-six patients (with 83 lesions [38 low-dose and 45 no-dose]) were evaluated in this analysis (Table 1). The most common tumor histology was adenocarcinoma (n = 13 [50%]), followed by squamous cell carcinoma (n = 3 [12%]). The most common high-dose tumor sites were lung (n = 17 [65%]) followed by liver (n = 6 [23%]). The most common sites for lesions receiving low-dose radiation were also lung (n = 15 [58%]) followed by liver (n = 6 [23%]) and abdomen (n = 3 [12%]).Tab1

Baseline Patient and Disease Characteristics and Best Responses after Low-Dose RT

Most patients (n = 20) received SABR to the high-dose targeted lesion, and the other 6 received intensity-modulated radiation (IMRT). In terms of the non-targeted lesions, 20 patients received low-dose radiation, defined as either scatter from the periphery of the high-dose field for the target lesion, and the other 6 patients received intentional low-dose radiation to 1 or more lesions in addition to lesions targeted with high-dose radiation. Ipilimumab (anti-CTLA-4) was given to 15 patients, pembrolizumab (anti-PD-1) to 8, and atezolizumab (anti-PDL1) to 2, either before or concurrent with radiation therapy. Twenty-two patients (85%) also had at least 1 lesion that did not receive any radiation (i.e., < 1 Gy), and those “no-dose” lesions were used as within-patient comparisons of response. Among those 22 patients, we compared 45 no-dose lesions against 33 low-dose lesions for this analysis.

In our first assessment, we asked if lesions that received low-dose radiation responded differently compared with lesions that were completely out of field. We found that 22 of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions (P = 0.001) (Fig. 1a). The median change for longest diameter size for low-dose lesions were − 38.5% (range − 100 to 68%) compared to 8% (range − 75 to 132%) in no-dose lesions (P < 0.0001) (Fig. 1b). The mean value of the low-dose radiation (i.e., either scatter or intentional) per lesion across all 26 patients was 7.3 Gy (range 1.1–19.4 Gy). The median time between immunotherapy and radiation was 27 days (range 0-105 days), the median time between response to RT was 39.5 days (range 10–153 days) and the median time from response to immunotherapy was 58 days (range 30–218 days). All lesions that responded to low-dose radiation had maintained this response at 6 months after treatment.Fig1Fig. 1

Low-dose radiation improves abscopal responses based on RECIST criteria. a, the percentage of lesions showing a clinical response based on RECIST criteria (CR/PR) was 53% (20 of 38) in low-dose lesions compared to 18% (8 of 45) no-dose lesions, ***P < 0.001. b, the median change for the sum of the longest diameter for low-dose lesions was − 38.5% (range − 100 to 68%) compared to 8% (range − 75 to 132%) in no-dose lesions, ****P < 0.0001. c, the percentage of lesions responding according to radiation dose. *P < 0.05. d, of the lesions from 22 patients with both no-dose (n = 45) and low-dose (n = 33) lesions, 12 lesions (36%) had low-dose-only responses at 6 months, and two (4%) had no-dose-only responses. e, Waterfall plot of no-dose tumor responses in patients having both lesion types. f, Waterfall plot of low-dose tumor responses in patients having both lesion types. g, Waterfall plot of low-dose tumors receiving 5–10 Gy in patients having both lesion types. h, Waterfall plot of low-dose tumors with NSCLC histology

To date, the rationale for using low-dose radiation (doses below the threshold thought to physically damage DNA or kill cancer cells directly) to enhance immune-cell killing in combination with immunotherapy has been largely theoretical. By evaluating patients being treated in three ongoing prospective clinical trials, and by focusing on lesions treated with low-dose radiation and entirely unirradiated lesions, this preliminary assessment suggests that lesions exposed to low-dose radiation experience clinically meaningful reductions in size relative to lesions that receive no radiation.

These results have notable implications for addressing a problem that has troubled onco-immunology for years, that is, how to turn abscopal responses from rare, inconsistent, and incidental findings to those that can be deliberately induced. Given metastatic disease remains mostly non-curable, factors that promote abscopal responses are actively being sought, as are ways to manipulate those factors in ways that reliably induce these effects in patients [7].

It is becoming increasingly apparent that the tumor stroma provides a substantially hostile environment to the antitumoral immune system, largely by means of cellular signaling and metabolic/transcriptional changes. Although manipulating the tumor stroma in efforts to enhance abscopal responses has been difficult, low-dose radiation may accomplish this by modulating the tumor stroma. Preclinical studies have shown the ability of low-dose radiation to polarize macrophages into a immunoproliferative M1 subtype, which enhances T-cell responses in this otherwise toxic tumor microenvironment [8]. Further, other findings, recently presented in abstract form [4], suggest that low-dose radiation may convert the stroma to a more favorable environment that induces homing of T lymphocytes, perhaps via reducing TGF-β signaling, which in turn results in decreased immunosuppressive cell signaling. Our findings offer a clinical proof-of-principle for this concept, given that lesions that did not receive radiation responded only if another lesion in the same patient had responded to low-dose radiation. This also suggests a potential way of inducing systemic responses by using local therapy [9].

This work is an integral component of the combined low-dose and high-dose radiation concept now being tested prospectively in NCT02710253, one of the three trials from which the current study dataset was derived. In this approach, high-dose radiation is given together with immune checkpoint inhibitors and with deliberate delivery of low-dose radiation, ideally to all known sites of disease. The assumption is that high-dose radiation acts to directly kill tumors, increase antigen release, and prime T cells; these newly primed T lymphocytes are further stimulated by the immunotherapeutic agents, which also prevent T-cell exhaustion. Theoretically, introducing the simultaneous delivery of low-dose radiation to other tumors throughout the body would modulate the tumor stroma throughout the body so as to facilitate infiltration of tumors by the primed T lymphocytes, which must come in direct contact with tumor cells to kill them and instigate further antigen release (Fig. 4).Fig4Fig. 4

Visual representation of two uses of radiation and how low-dose radiation and high-dose radiation affect the immune cell cycle. High-dose radiation is beneficial in directly killing primary tumor cells (1), which allows antigen release (2) and leads to T-cell priming (3). Immunotherapy decreases T-cell exhaustion and enhances lymphocyte trafficking to secondary tumors (4). Low-dose radiation, by contrast, modulated the tumor stroma and enhances infiltration of natural killer (NK) cells and T cells into secondary tumor sites (5), leading to enhanced immune-cell recognition of tumor cells (6) and resulting in ongoing tumor cell killing (1) and antigen release (2). Abbreviations: DAMPs, danger-associated molecular patterns; MHC1, major histocompatibility complex 1; ICOS, the immune checkpoint ‘inducible co-stimulator’; MDSCs, myeloid-derived suppressor cells; Tregs, T regulatory cells; TGF-β, tumor growth factor-beta; TAMs, tumor-associated macrophages

In conclusion, this report further demonstrates the effects of low-dose radiation in combination with high-dose radiation and immunotherapy. Low-dose radiation appears to provide beneficial responses in secondary tumors and may yield durable systemic responses to immunotherapy. Further prospective investigations are warranted to evaluate the efficacy of this approach.