Page 12 - TD-4-1

Tumor Discovery EpCAM-targeting cancer immunotherapies

5. Immunocytokines 6. Recombinant immunotoxins (rITs)

Immunocytokines are antibody-cytokine recombinant rITs are an emerging class of anticancer therapeutics
fusion proteins, with the potential to selectively localize involving the genetic fusion of antigen-specific antibodies
19
at tumor sites and to stimulate localized and systemic or cytokines to plant or bacterial toxins. As a subclass
anticancer immunity. 14,15 To date, one anti-EpCAM of anticancer protein therapeutics, rITs specifically target
immunocytokine has undergone clinical evaluation. and cleave a designated substrate, ultimately inducing
Tucotuzumab celmoleukin-interleukin-2 (huKS-IL2) is apoptosis. The development of EpCAM-targeting rITs has
an anti-EpCAM fusion protein consisting of a humanized reached various degrees of clinical success. An example is
antibody specific for EpCAM linked at its Fc end to two opportuzumab monatox (VB4-845), which was evaluated
molecules of IL2. 16,17 A phase 1b clinical study assessed in patients with non-muscle-invasive bladder cancer
the safety and unraveled the maximum tolerated dose (NMIBC) refractory to or intolerant of Bacillus Calmette–
(MTD) of huKS-IL2 following a single low-dose of Guerin (BCG). VB4-845 is a recombinant fusion protein
cyclophosphamide in patients with EpCAM-expressing that targets EpCAM-positive cancer cells. It is made up
17
advanced solid cancers. The investigators evaluated of an anti-EpCAM humanized single-chain variable
the immunogenicity, antitumor, biological activity, and fragment (scFv) linked to a truncated form of Pseudomonas
PK profiles of the fusion protein. The study recruited exotoxin A (ETA252 – 608) that lacks the cell-binding
20
22 patients aged >18 years, who had advanced or domain. Regarding bacterial-based rITs, the mode of
recurrent EpCAM-positive (25% or higher) solid tumors. action of VB4-845 is through antigen-specific binding and
The patients underwent up to six cycles of treatment. The endocytosis into the cytosol, followed by the release of the
treatment was 300 mg/m cyclophosphamide on day 1 toxin through escape from endosomal cleavage, leading
2
21
and then increasing doses of 0.5 – 4.0 mg/m intravenous to inhibition of EF1 protein synthesis and cell death. A
2
continuous infusion of huKS-IL2 over 4 h the following phase I dose-escalation clinical study was conducted to
day and for 3 days within the 21-day cycle. The most investigate the MTD of VB4-845. As a secondary aim of the
common adverse reaction was transient lymphopenia clinical study, the authors investigated the immunogenicity,
safety, efficacy, tolerability, and PKs profile of VB4-845.
22,23
(which is considered grade 3 and 4 adverse reactions), The study recruited 64 participants (>18 years old), with
18
whereas nausea, pyrexia, rash, chills, diarrhea, fatigue, early-stage transitional cell carcinoma or in situ carcinoma,
headache, vomiting, hypophosphatemia, increased serum grade 2/3, who were refractory and intolerant to BCG
creatinine, and hypotension were the frequently observed therapy. Other inclusion criteria of the study were patients
minor adverse effects. In addition, 88.5% of patients had with adequate renal, hepatic, and hematological function.
a transient immune response to huKS-IL2. The authors Second, the recruitment of patients of childbearing age
established that the MTD was 3.0 mg/m for huKS-IL2 was expected to undergo contraceptives before and during
2
when combined with 300 mg/m cyclophosphamide, with the study. The rIT was administered intravesically for 6
2
dose-limiting myelosuppression noted at higher dose consecutive weeks, in increasing weekly doses (from 0.1
concentrations. The dose-limiting toxicity was attributed to 30.16 mg) through an indwelling urinary catheter. The
to non-specific activities of the cyclophosphamide because study participants were tracked for 4 – 6 weeks following
the huKS-IL2 exposure was not dose-proportional but treatment and assessed at the 12 week. After the study,
th
dose-dependent with negligible off-target accumulation. 64% of patients had adverse reactions, with 33% facing
A transient immune response to huKS-IL2 was noted pharyngolaryngeal pain, bladder spasm, urinary tract
for most patients (mainly anti-idiotype or antilinker infection, incontinence, and nocturia. These reactions were
antibody induction) without an established association believed to have resulted from concomitant medications. In
of these responses to the neutralizing effect of the addition, a third of patients experienced mild-to-moderate
immunocytokine. The best response was stable disease adverse reactions that were believed to be caused directly
which lasted for more than four cycles in three out by rIT including dysuria and hematuria, fatigue, loss of
of 22 patients. The combination of huKS-IL2 and appetite, fever and chills, myalgia, nausea, and dizziness.
cyclophosphamide was well-tolerated without beneficial However, these reactions did not increase in frequency
clinical endpoints. This study showed that there is a with dose. Following the last dose of VB4-845, one patient
potential for huKS-IL2 as an immunotherapeutic in died from cardiac failure, and his demise was unrelated to
combination with low-dose cyclophosphamide. The the effects of the rIT. Overall, the adverse reactions were
combination of these drugs in patients with advanced mild and adequately managed. The authors were unable
tumors was deemed to be a feasible and safe treatment to determine an MTD for VB4-845, and the apparent
strategy. lack of relationship between the adverse reactions and the

Volume 4 Issue 1 (2025) 4 doi: 10.36922/td.4926