Tuesday, February 9, 2016

Tumor-tailored "immunogenic" chemotherapy sensitizes tumor to immune attack

Today journal Immunity published an excellent preclinical research study about tumor immunity. In this paper the authors conducted methodical analyses of the role of tumor-tailored chemotherapy on its immunogenicity and synergy with checkpoint immunotherapy.

It is now universally accepted that T cell-oriented immunotherapy (with anti-PD1, anti-CTLA4) represents important medical progress in treatment of [solid] cancers. Still, not every cancer type is responsive to such immunotherapy. However, this is about to change when personalized, molecular evidence-based tumor therapy becomes widely affordable [technology already exists]. This paper is an example how this would be accomplished.

For this study the authors have used KP lung adenocarcinoma mouse model that express "endogenous mutant Kras and deleted Trp53 alleles in lung epithelial cells upon administration of adenovirus expressing Cre recombinase". This tumor was non-responsive to T cell infiltration or checkpoint inhibition or combination of paclitaxel (Ptax) and carboplatin (Carbo), Ptax-Carbo (chemotherapeutics).

Next, the authors hypothesized that this non-responsiveness could be due to lack of "immunogenicity" of KP cells. To examine this, they conducted in vitro "immunogenic cell death" test with several KP cell lines using FDA approved chemotherapy drugs. High mobility group box 1 (HMGB1) release was used as a surrogate marker for chemotherapy drug-induced tumor cell immunogenicity. They showed that combination of mafosfamide (Maf), which is the active metabolite of cyclophosphamide (Cyc), and oxaliplatin (Oxa) stimulated HMGB1 release by all KP tumor cell lines both in vitro and in vivo.

As expected, in vivo application of Oxa-Cyc combination reduced tumor burden in KP mice.

Effect of Oxa-Cyc was mediated via T cells since its effect was abolished in T cell-deficient RAG KO mice or in KP mice depleted of CD8 T cells.

Interestingly, Oxa-Cyc effect was also depended on TLR4 expression on CD11b+/CD11c+ myeloid cells.
More importantly, the authors showed that Oxa-Cyc treatment synergized with checkpoint inhibitors, anti-PD-1 + anti-CTLA-4, to control lung tumor burden in KP mice.

Finally, the authors expanded this observation to include two other tumor types, MCA205 fibrosarcoma and CT26 colon carcinoma, and showed selective tumor-tailored chemotherapy synergized with checkpoint inhibitors to control tumor burden in these models as well.

In summary, the results in this study indicate that checkpoint inhibitors alone may not provide any benefits to patients where tumor lack T cell infiltration due to absence of tumor "immunogenic death". However, application of selective, tumor-tailored chemotherapeutics (to induce tumor immunogenic cell death and attract T cells) would synergize with checkpoint inhibitors (working then on tumor-infiltrating T cells) in non-responsive tumor patients and improve clinical outcome of the tumor therapy. In practical terms this would mean development of in vitro tests to examine patient's tumor cell "immunogenicity" response to chemotherapeutics on a personalized basis.

David Usharauli

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