Commentary

The advent of immunotherapy has given rise to a spectrum of immune-mediated events including pseudoprogression or reactive tumor inflammation.1 These terms, which refer to the initial appearance of new or enlarged lesions on imaging that subsequently stabilize or regress weeks or even months later have been described as an infrequent pattern of response (3–5%) with immune checkpoint inhibitors (ICIs).2 3 However, in our experience with AdAPT-001, an oncolytic adenovirus, which expresses a transforming growth factor-beta (TGF-β) trap that binds to and neutralizes the potently immunosuppressive and profibrotic cytokine, TGF-β,4–6 pseudoprogression (PsP) may occur at a much higher frequency than with ICIs.

In treatment-refractory patients that have received multiple doses of locally injected AdAPT-001 on the Phase 1/2 BETA PRIME trial (NCT04673942),7 we estimate that 45% (20/44) have experienced PsP or reactive tumor inflammation8 9—that is, a temporary or prolonged enlargement of lesions with or without improved clinical symptoms (but more often with symptomatic improvement) and whether or not the Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 criteria for the progressive disease was strictly met followed by delayed shrinkage sometimes months later.

Also, of six patients with eccrine carcinoma, chordoma, breast angiosarcoma, arm/breast melanoma, dedifferentiated liposarcoma, and alveolar soft part sarcoma who were treated beyond RECIST progressive disease only the eccrine adenocarcinoma, chordoma, and breast angiosarcoma, that is, 3/6 or 50% of them, went on to show clinical benefit; as of this date, May 01, 2024, the treatment of all three patients is ongoing with durations ranging from 4 to 14 months post RECIST-progression.

Overall, PsP carries a favorable prognosis, but also the potential for mass effect-like complications especially if it is extreme or excessive,10 as occurred in the case of one AdAPT-001-treated patient with squamous cell carcinoma of the neck (see online supplemental figure 1). Despite extensive treatment-induced necrosis and sloughing, this tumor enlarged to such a degree, as shown below, that it threatened to impinge on vital neurovascular structures in the neck, which prompted the investigator, out of caution, to discontinue the patient from the trial. Sadly, the patient died 3 months later from tumor progression.

Three representative and favorable examples of PsP in the BETA PRIME trial are as follows. The first is a patient in their 70s who presented with multiple lesions on the left leg due to metastatic eccrine carcinoma. These lesions were accompanied by significant left lower limb lymphedema, which led to falls, reduced mobility, social isolation, and the need for mobility aides. After approximately 4 months of treatment or seven injections of AdAPT-001, the patient experienced a significant temporary inflammatory reaction, resembling a tumor flare, also known as PsP (figure 1). The lesions on the heel, outside ankle, and hamstring were visibly enlarged at 4 months, however, because the patient-reported significant symptomatic improvement with decreased pain, mobility and swelling, the decision was made to continue treatment. At month 5, lesions began to shrink, and led to what is currently an ongoing durable partial response.

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Figure 1

Response of back heel lesions to AdAPT-001 over time with lesion disappearance.

The second example (see online supplemental figure 2) is a patient in their 30s with papillary thyroid carcinoma that was limited to a single lesion. After approximately 4 months of treatment or eight injections of AdAPT-001, the patient experienced an inflammatory reaction, resembling a tumor flare, with an increase in the size of the tumor by 11% when assessed by RECIST V.1.1 criteria. At month 7, the lesion qualified for a partial response based on a reduction of overall tumor size by 31.9%. The patient has continued therapy and on the following CT scan achieved a confirmed partial response with a maximum reduction of 36.2% from baseline.

The third example (figure 2) is a patient with angiosarcoma of the cheek, who received AdAPT-001 plus a checkpoint inhibitor, nivolumab, to which he had previously been resistant. After 1 month on treatment, the patient’s lesions met RECIST criteria for progression. However, because the patient reported less bleeding, fatigue, and pain, he was allowed to remain in the study. By month 3 the lesions began to regress and by month 9 they had all but disappeared, as shown below.

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Figure 2

Regression of angiosarcoma of the cheek after initial and dramatic enlargement.

Most patients with PsP in the study have followed this pattern of tumor enlargement at around 1 month followed by stabilization or regression starting at around month 3. The one feature of study that most reliably distinguished patients with true progression from those with PsP is that the latter, with few exceptions, reported better well-being and functional status, and this was the case even for the patient with head and neck cancer with “extreme pseudoprogression”, pictured in online supplemental figure 1.

From a certain perspective, it makes sense that AdAPT-001-mediated PsP may occur with higher frequency and last longer than with ICIs since the direct antitumor effects that locally administered AdAPT-001 induces differ in intensity (and possibly duration) from the indirect antitumor effects of the systemically administered ICIs. The rapid replication kinetics of the minimally attenuated AdAPT-001 virus closely mimic that of wild-type virus, which is inherently inflammatory.11 12 From preclinical experiments, the rapidity of virus replication and spread contribute to its persistence.13 It is this persistently strong immune stimulus combined with the immunogenic cell death that results from oncolysis, the release of inflammatory cytokines, and the TGF-β trap-mediated reversal of immunosuppression that likely contribute to the intensity of cytotoxic T-cell infiltration,14 as shown in online supplemental figure 3, and, by extension, to PsP. Also, in preclinical studies with immunocompetent mice heterotopically implanted syngeneic mouse tumors paradoxically enlarged at the start of treatment with AdAPT-001 prior to regression 1 week later, which is reminiscent of the delayed responses that occurred in the clinic.15

Another localized therapy that, like AdAPT-001, directly induces tumor cell death and activates anticancer immunity is radiotherapy, where the incidence of PsP in glioblastoma from radiotherapy is approximately 30%.16

The purpose of this commentary is to spotlight the higher frequency of PsP and delayed responses that we have observed with AdAPT-001 since oncologists are trained to equate new or enlarged lesions with unequivocal progression; this may lead them to prematurely discontinue patients from trial that would have otherwise derived clinical benefit even though the BETA PRIME protocol allows for treatment beyond progression with RECIST criteria. Adjuncts or aids to help diagnose PsP include biopsy, measurement of cell-free DNA, positron emission tomography (PET), a nuclear medicine imaging method, and ultrasound, none of which were attempted in this clinical study for reasons of patient refusal, feasibility, or cost.17

In the end, however, due to the paucity and often the indeterminacy of these diagnostic aids, it is essentially up to the clinician to determine whether PsP has occurred. Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) criteria that are used to differentiate pseudoprogression from true progression were not mandated in this study, but in practice, the patients who benefited from treatment beyond progression were managed similarly to iRECIST with frequent clinical and radiological reassessment soon after the scan that initially suggested progression and continuation of treatment provided one or more clinical characteristics were present: better performance status or less deterioration of performance status, clinical stability, lower incidence of new lesions, stabilization or resolution of existing lesions, and/or improved quality of life. Since the presence of PsP is potentially a surrogate for clinical benefit and for increased survival,18 clinicians would do well to be on the lookout for it with AdAPT-001 either alone or in combination with checkpoint inhibitors where PsP may occur with an even greater frequency and to maintain a high index of suspicion during treatment so that patients are appropriately managed.