Wednesday, July 20, 2016

Report on intratumoral IL-2 with intratumoral ipi for nonresectable Stage III/IV melanoma

I first reported on this treatment in this link from ASCO 2015:

ASCO 2015: Intralesional therapy for melanoma

Within, among other reports, there is this:

A phase 1 study of intratumoral injection of ipilimumab and interleukin-2 in patients with unresectable stage III-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Bowen, Meek, Williams, Grossman, et al.

Intratumoral IL-2 is highly effective and well tolerated, but does not generate systemic immunity or response in untreated lesions.  IV ipi lowers the threshold for T cell activation leading to a durable clinical response in a minority of melanoma patients, but is associated with potentially severe toxicities.  Since IV ipi doesn't have tissue distribution, circulating anti-tumor T cells activated by the drug may differ greatly from tumor infiltrating lymphocytes activated by INTRATUMORAL ipi in terms of quantity and quality.  Therefore, we hypothesized that a combination of IT IL-2 and IT ipi would effectively hyperactivate and expand TILs to engender systemic immunity with minimal toxicity.   This phase 1 dose escalation trial for ipi and fixed dose IL-2 involved patients with unresectable stage III/IV melanoma and at least one injectable lesions.  A single lesion in each patient was treated with IL-2 IT TIW for 2 wks, then BIW for 6 wks, with escalating doses of ipi IT weekly for 8 weeks.  RESULTS:  12 patients were treated with 3 ipi dose levels.  Treatments were well tolerated.  The only grade 3 toxicity was injection site/tumor necrosis, not dose limiting.  Other toxicities were grade 1.  An abscopal effect (response in a least 1 NON-injected lesion) was seen in 9/12 patients (75%).  10 patients were evaluable for immune response:  4 with partial regression (40%) and 6 had progressive disease, though later one PD was later found to be a complete response by resection.  The 2 nonevaluable patients had regression of multiple skin lesions.  An increase in the frequency of IFN producing CD8+ T cell was detected in 6/8 abscopal responders.  Tbet+ and granzyme B+ CD8+ T cells were observed in 4/5 and 3/5 responders tested, respectively.  Researchers plan to conduct a phase II trial using IT Ipi/IL-2 in conjunction with systemic immunotherapy.

Above, these researchers state that they are planning to conduct a phase II trial with this treatment process, possibly combined with systemic therapy...but this (below) was recently published:  (I left all author names so you can note the researchers.)

A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma.  Ray, Williams, Meek, Bowen, Grossmann, Andtbacka, Bowles, Hyngstrom, Leachman, Grossman, Bowen, Holmen, VanBrocklin, Suneja, Khong.  Oncotarget. 2016 Jul 6.

Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy.

There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients, an abscopal response was seen in 89%. The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% and 50%, respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses.

Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks.

Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.

So...this appears to be the same 12 patients originally reported on....perhaps with a bit more information upon follow-up...with the abscopal response rate being reported at 89% vs the 75% noted in the earlier report.  Or maybe they just needed to have one more article published for their advancement in academia?  Who knows?  Still looks promising.  Don't know why they haven't done a phase II study.  Though I did find this....a phase II study conducted in Germany with no results publishes as of July 6: - intratumoral ipilimumab and interleukin 2

If I find any more intel, I'll let you know!  For what it's worth. - c

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