As of June 1, 2024, when the ASCO abstract was presented, the overall objective response rate (ORR) on the BETA PRIME clinical trial (ClinicalTrials.gov NCT04673942) in an immunorefractory advanced cancer population that received 1×1012 viral particles of AdAPT-001 every 2 weeks plus a checkpoint inhibitor (CI) like the PD-1 inhibitor nivolumab was 29.1 % (7/24).1 2 This ORR included one clinical complete response in an angiosarcoma patient and six partial responses in three sarcoma patients, one head and neck cancer patient, one squamous carcinoma patient, and one triple negative breast cancer patient without any dose-limiting toxicities or related severe adverse events. In addition, a 62.5% clinical benefit rate consisting of complete or partial responses or stable disease was observed. A few of the clinical images that document these systemic responses are shown in figure 1a–c.

Clinical images from the phase 1/2 BETA PRIME clinical trial. (a) Patient with angiosarcoma of the glabella; (b) patient with myxosarcoma of the forearm; (c) patient with angiosarcoma of the axilla that received 1×1012 viral particles of AdAPT-001 every 2 weeks plus 240 mg of nivolumab every 2 weeks.

A substantial paradigm shift is underway in medical oncology with the use of immunotherapies, whose function is to harness the selective cytotoxic potential of the immune system to fight cancer with limited toxicity to normal tissue.3 4 CIs appear to function preferentially in T-cell inflamed or immunologically “hot” tumors; however, the high occurrence of immunosuppressed or immunologically “cold” tumors imposes a “ceiling” on response rates, generally in the range of 20%–40%.5 To overcome the limitation of single-agent CIs, several combination therapies are under evaluation. But such combinations, promising though they are, usually come at the expense of unacceptably high rates of grade 3 and 4 autoimmune-like toxicities.3 Dr Conley’s lecture focused on AdAPT-001, an armed oncolytic virus that expresses a TGF-β receptor trap and that, in clinical studies, demonstrates the potential to augment immune therapies and limit their toxicity.

Oncolytic viruses mediate antitumor activity through infection and replication of the virus selectively in tumor cells with subsequent lysis of tumor cells and release of additional tumor-selective infectious viral particles. These newly released viral particles may propagate the infection to any remaining viable tumor cells that are accessible.3 During natural infection, critical counter-regulatory cytokines are expressed to prevent immunopathology. Tumors, which often arise in the context of chronic irritation and persistent inflammation, also frequently overexpress counter-regulatory cytokines like TGF-β that are potently immunosuppressive.

Ominously, radiation and chemotherapy can induce TGF-β, betokening resistance to these anticancer therapies.

AdAPT-001 differs from other oncolytic viruses because it expresses a transgene that codes for a TGF-β receptor trap, which neutralizes active TGF-β, whether endogenous to the tumor microenvironment (TME) or therapeutically induced. TGF-β neutralization is essential for activation of natural killer cells, T cells, B cells, dendritic cells, M1 macrophages, and granulocytes, and antigen-specific tumor clearance. Hence, in addition to fast replication kinetics, it is the potent expression of the TGF-β trap that helps to establish a sustained immune stimulatory state within the TME.6 The clinical data presented shows that AdAPT-001 can sensitize tumors to immune CIs, even tumors that were previously refractory or resistant to CIs (figure 1a–c).7

Moreover, the results presented clearly demonstrate that uninjected, metastatic lesions responded to treatment with AdAPT-001, and an example in a patient with melanoma is shown (figure 1b). These results demonstrate that intralesional administration of AdAPT-001 increases the susceptibility of cancer cells to elimination when used alone or in combination with an adjunctive therapy like CIs and that a systemic therapeutic response is elicited.

One of the key challenges in oncology is how to make immune CIs more broadly effective. The evidence suggests that better response rates (RR) and overall survival (OS) can be achieved by combining anti-PD-1/L1 therapies with various other therapies such as chemotherapy or other CIs; however, these combinations often result in substantial increases in toxicity.8 Also, despite their relative non-toxicity, previous clinical trials with other intralesional oncolytic viruses like T-VEC, have not always improved RR and OS.9 By contrast, AdAPT-001, which, based on preclinical data and the clinical data presented by Dr Conley, seems to reduce therapeutic resistance especially to CIs, is associated with low toxicity and demonstrates local and systemic responses.10 Preclinical experiments have demonstrated that the addition of the TGF-β receptor trap to the oncolytic virus maximizes the therapeutic activity of AdAPT-001, as shown in figure 2.

Contribution of the transforming growth factor beta receptor (TGF-βR) trap to the anticancer activity of AdAPT-001. This experiment involved the use of mouseAdAPT-001 (mAdAPT-001) with a mouse TGF-βR and IgG fusion transgene. 129S4/SvJaeJ mice were injected with 5×105 ADS-12 cells subcutaneously and allowed to form tumors. When the average tumor size reached ~150 mm3, ADS-12 tumors were treated with three intratumoral doses of oncolytic virus without a TGF-β trap transgene (5×107 PFU per dose), mAdAPT-001(5×107 PFU per dose) or phosphate-buffered saline on days 0, 4, and 8. Each line represents tumor volume of one mouse, n=10 per group.

Currently, no biomarkers are available to predict which tumors are most likely to respond to the combination of AdAPT-001 and CIs. However, serum measurement of soluble PD-L1, PD-1, and TGF-β are currently under investigation as biomarkers for this combination.

Consent obtained directly from patient(s).

This study involves human participants and the protocol for BETA PRIME and the participant informed consent received approval from the was approved by WIRB-Copernicus Group, WCG IRB 20203029. Participants gave informed consent to participate in the study before taking part.