TY - JOUR
T1 - Intratumoral injection of clostridium novyi-NT spores in patients with treatment-refractory advanced solid tumors
AU - Janku, Filip
AU - Zhang, Halle Huihong
AU - Pezeshki, Abdulmohammad
AU - Goel, Sanjay
AU - Murthy, Ravi
AU - Wang-Gillam, Andrea
AU - Shepard, Dale R.
AU - Helgason, Thorunn
AU - Masters, Tyler
AU - Hong, David S.
AU - Piha-Paul, Sarina A.
AU - Karp, Daniel D.
AU - Klang, Mark
AU - Huang, Steven Y.
AU - Sakamuri, Divya
AU - Raina, Anjali
AU - Torrisi, Jean
AU - Solomon, Stephen B.
AU - Weissfeld, Alice
AU - Trevino, Ernest
AU - DeCrescenzo, Gary
AU - Collins, Amanda
AU - Miller, Maria
AU - Salstrom, Jennifer L.
AU - Korn, Ronald L.
AU - Zhang, Linping
AU - Saha, Saurabh
AU - Leontovich, Alexey A.
AU - Tung, David
AU - Kreider, Brent
AU - Varterasian, Mary
AU - Khazaie, Khashayarsha
AU - Gounder, Mrinal M.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 104 to 3 106 spores, 3þ3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n ¼ 2) and grade 4 gas gangrene (n ¼ 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n ¼ 1), limb abscess (n ¼ 1), soft-tissue infection (n ¼ 1), respiratory insufficiency (n ¼ 1), and rash (n ¼ 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.
AB - Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 104 to 3 106 spores, 3þ3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n ¼ 2) and grade 4 gas gangrene (n ¼ 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n ¼ 1), limb abscess (n ¼ 1), soft-tissue infection (n ¼ 1), respiratory insufficiency (n ¼ 1), and rash (n ¼ 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.
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U2 - 10.1158/1078-0432.CCR-20-2065
DO - 10.1158/1078-0432.CCR-20-2065
M3 - Article
C2 - 33046513
AN - SCOPUS:85100334775
SN - 1078-0432
VL - 27
SP - 96
EP - 106
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -