CIMT 2016 "Mechanisms of efficacy in cancer immunotherapy"

For 14 years now, the largest meeting in Europe focused on cancer immunotherapies, the CIMT Annual Meeting, gathers the knowledge and progress of academia, scientific organizations, industry and clinical research. It provides a comprehensive picture of the current status in the tremendous therapeutic potential of immuno-oncology through the excellent invited speakers presentations and expert panel discussions, further completed by poster exhibits and selected short talk sessions.

Dr. Pittet (Harvard Medical School) opened the first plenary session of this year’s conference by quoting Jimmy Carter, addressing a topic to which many presenters returned repeatedly throughout the conference: “Why do some people respond, but others don’t? Can we find new approaches for non-responders?” Although cancer treatment is nowadays heading towards personalized treatment based on unique molecular tumor characteristics, this is not yet the case for cancer immunotherapy.

The tumor microenvironment with its complex interactions between stromal, immune and cancer cells may provide some clues in filling the gaps of lacking knowledge and finding new targets for cancer treatment. Tumor cells create their own microenvironment, rather than the organ in which the tumor is located. Pittet focused on the role of myeloid cells in cancer, in particular macrophages. He explained how tumor cells communicate remotely with hematopoietic stem cells and progenitor cells in the bone marrow via the release of AngII, inducing the production of inflammatory monocytes (CCR2+ macrophages). As these are then mobilized into the circulation and trafficked towards the tumor cells, they differentiate into so-called tumor-associated macrophages (TAM) that infiltrate in the tumor stroma and create a tumor-promoting environment by inducing immunosuppression, angiogenesis and tissue remodeling. In contrast, Pittet illustrated how myeloid cells are also capable to augment anti-tumor immunity. Subcapsular sinus (SCS) macrophages, located below the capsule of tumor draining lymph nodes, has been shown to suppress melanoma cancer cells by restricting the interaction between tumor-derived vesicles and B-cells.

As a target for cancer immunotherapy, key may be indeed to stimulate the adaptive anti-tumor immunogenic “M1 like” monocytes, while the inflammatory pro-tumor immune suppressive “M2 like” monocytes are kept under control.

Tumor stroma changes over the course of tumor development, characterized by the ‘stromogenic switch’, in which fibroblast activation protein (FAP) on stroma cells and part of M2-like TAMs plays a pivotal role (Puré, University of Pennsylvania). Hereby, the stroma is remodeled into reactive tissue, characterized by a chronic inflammatory state and fibroproliferative disease, and hence encouraging a pro-tumorigenic environment. Puré showed that the activated fibroblasts (versus quiescent fibroblasts) resulted in both a lower overall survival and progression-free survival (PFS) in patients. Preclinical models demonstrate that FAP-specific chimeric antigen receptor (CAR) T cells can be engineered that effectively target these FAP+ cells and are able to inhibit tumor growth. Possible cancer indications may be breast cancer, lung cancer and pancreatic cancer.

After last year’s presentation of neoantigen-specific T cell responses in effective immunotherapies by Ton Schumacher, this year mutated tumor-specific neoepitopes and the usage of immuno- and/or tumor modulating antibodies such as CTLA-4 and PD-1/PD-L1 predominated all sessions and posters. Cell therapies were widely represented by CAR approaches and vaccination strategies including dendritic cell (DC) strategies.

In recent years, several checkpoint inhibitors have been approved, including ipilimumab (2011), nivolumab and pembrolizumab (2014) for melanoma, pembrolizumab and nivolumab for non-small cell lung cancer (2015), and nivolumab for renal cell carcinoma (2015), respectively. Currently, approximately 600 clinical trials with checkpoint blocking therapy (CBT) are ongoing and durable responses have been demonstrated for various tumor types.

CD8 T cell infiltration in tumors has been shown to increase the sensitivity for CBT (Pittet, Harvard Medical School). The conventional chemotherapy combination of paclitaxel and carboplatin appears to be less effective when compared to the combination of oxaliplatin and cyclophosphamide in inducing CD8 T-cell infiltration, which was demonstrated for a non-responder mouse model of K-ras mutated lung adenocarcinoma. This indicates that pre-treatment with chemotherapy may be promising to increase the efficacy of CBT. In addition, diverse chemotherapeutical agents have been investigated in the ability to down-regulate anti-apoptotic AREG, which was effectively accomplished by 5-FU, gemcitabine, docetaxel, paclitaxel, oxaliplatin, cisplatin, etoposide and irinotecan, but not cyclophosphamide, fludarabine, doxorubicin, bevacizumab, carboplatin (Bronte, University of Verona).

CBT induces long remissions in refractory Hodgkin’s Lymphoma, which may be attributable to PD-L1/2 expression on Reed-Sternberg cells (Meyer, St Johannes Hospital Dortmund, 'sponsored by Bristol-Myers-Squib'). Also, in some NHL, CBT has shown to be effective. The best context or combination for CBT yet needs to be defined.

Dr. Grabbe (University Medical Center Mainz, sponsored by Bristol-Myers Squibb) summarized the results of the phase II CHECKMATE-064 study, in which two arms of patients with advanced melanoma received either nivolumab prior to ipilimumab or in reversed order. This study showed that first treatment with anti-PD1 monotherapy was more effective in providing a durable long term survival in advanced melanoma. Another study in previously untreated patients with metastatic melanoma (CHECKMATE-067, Larkin et al, NEJM 2015), investigated the combination therapy of anti-CTLA4 and anti-PD1 (ipilimumab and nivolumab) versus both agents alone. Nivolumab, either as monotherapy or combined with ipilimumab, demonstrated significantly longer progression-free survival (6.9 months 95%CI 4.3-9.5, 11.5 months 95%CI 8.9-16.7, respectively) than ipilimumab alone (2.9 months 95%CI 2.8-3.4). Still, Grabbe pointed out that there may be an indication for anti-PD1 monotherapy, for example in patients with pre-existent autoimmune signature, in case of multimorbidity, or in patients with limited disease.  Interestingly, efficacy showed to be regardless of the PD-L1 status of the tumor, showing the limited predictive value of PD-L1 as biomarker. Other predictors are needed for durable cancer control, revealing which patient will benefit from a certain treatment and which patient will not.

The increase of titles related to RNA-based therapeutics and vaccines within the CIMT poster session compared to previous years, highlighted the increased focus on RNA approaches. While a large portion of current articles anyhow relate to the topic of mRNA vaccination, some details will be given in our second blog (CIMT 2016 - Rise of mRNA therapeutics, a relatively new class of treatment) addressing in vitro transcribed-RNA itself and the vaccination approaches associated.

References:

Bronte V, Murray PJ. Understanding local macrophage phenotypes in disease: modulating macrophage function to treat cancer. Nat Med. 2015 Feb;21(2):117-9. doi: 10.1038/nm.3794. PMID: 25654601.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. doi: 10.1056/NEJMoa1504030. Epub 2015 May 31. Pubmed PMID: 26027431.

Lo A, Wang LC, Scholler J, et al. Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells. Cancer Res. 2015 Jul 15;75(14):2800-10. doi: 10.1158/0008-5472.CAN-14-3041. Epub 2015 May 15. PubMed PMID: 25979873.

Pucci F, Garris C, Lai CP et al. SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science. 2016 Apr 8;352(6282):242-6. doi: 10.1126/science.aaf1328. Epub 2016 Mar 17. PubMed PMID: 26989197.

Ugel S, Peranzoni E, Desantis G et al. Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Rep. 2012 Sep 27;2(3):628-39. doi: 10.1016/j.celrep.2012.08.006. Epub 2012 Sep 6. PubMed PMID: 22959433.

Image: Adapted from Bronte and Murray, Nat Med 2015