Background Multiplex Combination Intratumoral Immunotherapy (MCII) is a cancer treatment that appears to offer advantages over conventional systemic immunotherapy, including higher disease control rate and more favorable adverse event profile. Identification of fibrous pseudotumor at the site of successfully-treated cancer (pseudostabilization) after MCII has not been previously described, and is often radiographically mistaken for cancer.

Methods Twelve patients with metastatic solid cancer and one with sacral chordoma were treated with monthly cycles of MCII (3–5 days of oral cyclophosphamide followed by cryoablation and intratumoral injection of ipilimumab, pembrolizumab, and cyclophosphamide; GM-CSF was subcutaneously administered daily for 4 weeks). Post-treatment biopsies were obtained at the treating physician’s discretion to confirm or refute the presence of residual cancer; a total of 7 patients were biopsied.

Results Radiographically-detected residual masses consisting of fibrous pseudotumor were identified at sites of MCII treatment in 3 of 7 biopsied patients (43%), all of whom had partial response (iPR). One patient each had 1, 2, and 3 tumors (total of 6), of which 5 of 6 were pure pseudotumor and one was pseudotumor with 10% embedded cancer by estimated volume. Two tumors had minimal scattered lymphocytes, but no other inflammation was observed. The masses invariably decreased in size from baseline cancer measurements, and all were interpreted by CT imaging as malignant. No pseudoprogression was observed in any patient.

Conclusions Fibrous pseudotumor is a common finding after Multiplex Combination Intratumoral Immunotherapy (MCII). Unlike pseudoprogression, in which there is enlargement from baseline, pseudostabilization is defined as stabilization or shrinkage, apparently resulting from transformation of the mass from cancer to fibrous pseudotumor. Biopsy is required to differentiate this finding from residual cancer, and we have modified our treatment protocol accordingly. Modification of iRECIST criteria is needed to accommodate this novel and frequent finding after MCII, relying on pathology data when available rather than imaging.

Trial Registration NCT04711371

Ethics Approval Ethics approval was granted by Institutional Review Board (Advarra, Columbia, MD; Pro 00045172). The study was also cleared by the US Food and Drug Administration (IND 151900). Each patient provided written informed consent prior to participation and prior to each treatment.