Adoptive T cell therapy in patients with recurrent ovarian cancer

The clinical outcome of standard treatment for patients with epithelial ovarian
cancer (EOC) is poor, with a 5-year survival rate of only 35%. Ovarian cancer
is a highly immunogenic tumor and good survival is tightly linked to the
presence of tumor-infiltrating CD8+ T cells and the absence of
immunosuppressive immune cells [Zhang et al, NEJM, 2003, Hwang,WT Gynecol Oncol
2012]. The clear correlation between T cell infiltration and disease
progression suggests that EOC may be sensitive to adoptive cell therapy by
infusion of ex-vivo expanded autologous Tumor Infiltrating Lymphocytes (TIL),
provided that immune suppression is reduced. Carboplatin+paclitaxel
chemotherapy is directly killing tumor cells, but was also shown to alleviate
immunosuppression for 2 weeks coinciding with enhanced T-cell immunity,
potentially creating a window of opportunity for T-cell based immunotherapy. In
addition, there is evidence that interferon alpha (IFNα) may not only work as a
low toxic preconditioning regimen that creates the space required for the
infused TIL, but that it also supports the TIL by sustaining their persistence
and indirectly their function via upregulation of HLA class I on tumor cells
and by decreasing the number of regulatory T cells.
Based on this we hypothesize that a synergistic clinical effect may be obtained
when TIL are administered during treatment with chemotherapy that might even be
increased when IFNα is added to the TIL infusion and chemotherapy.
We therefore propose to study the feasibility and safety of TIL administration
in the window of opportunity created by carboplatin-paclitaxel chemotherapy
with or without supportive IFNα. Furthermore, we will perform exploratory
studies to analyze and confirm the proposed underlying mechanisms.
.

Primary:
• Evaluate the safety of TIL, alone or with IFNα, in patients with recurrent
platinum sensitive EOC during standard chemotherapy (carboplatin and
paclitaxel).

Secondary:
• Evaluate signs of activity and underlying mechanisms (response rate, disease
control rate, progression free and overall survival, immune modulation by
chemotherapy and by IFNα, TIL and IFNα, as well as T-cell reactivity).

A prospective, single center, open label, phase I/II study.

Cohort 1 (n=3-6): Add TIL to standard chemotherapy (carboplatin+paclitaxel).
TIL will be administered 2 weeks after the 2nd, 3rd and 4th chemotherapy cycle

Cohort 2: (n=3-6) Add TIL plus IFNα to standard chemotherapy (carboplatin and
paclitaxel).
TIL will be administered 2 weeks after the 2nd, 3rd and 4th chemotherapy cycle
and IFNα will be administered for 12 weeks during the TIL therapy.

The risk of participation are toxicity of the TIL, with or without IFNα, when
added to standard chemotherapy.
For most patients, tissue will be obtained at primary surgery, while for some
patients an extra biopsy will be necessary.
An extra biopsy is painful but rarely gives a bleeding or infection.

Patients will have to come to the hospital for the TIL infusions and have to be
hospitalized for 24 h during the first TIL infusion.

Benefit:
Patients with recurrent ovarian cancer, have a poor prognosis for which further
improvement of alternative treatment
options is necessary. The study offers a chance to obtain clinical benefit in
these patients, that otherwise have a very bad prognosis.