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AACR19 Day 5 Update: Bispecific Antibodies, the Importance of “Helper” T Cells, and the Lloyd J. Old Award Lecture

The opening plenary session on Day 5 of the annual meeting of the American Association for Cancer Research focused on novel immunotherapy strategies that could potentially enable more patients with more types of cancer to benefit. Pablo Umaña, PhD, of the Roche Innovation Center in Switzerland, highlighted recent advances in bispecific T cell engager (BiTE) immunotherapies. By targeting markers on tumors as well as CD3, an important component of the T cell receptor, BiTEs can activate T cells, guide them to cancer cells, and stimulate their cancer-killing capabilities. Already, a BiTE targeting the CD19 marker associated with B cell cancers has been approved by the FDA for leukemia. Umaña first discussed a BiTE targeting CD20, another marker of B cells, that is being evaluated in a phase I trial for patients with B cell non-Hodgkin lymphoma. Of patients who received the 10mg dose, 57% responded, with 29% having complete responses, and another study is now evaluating this BiTE in combination with PD-L1 checkpoint immunotherapy.

Pablo Umaña, PhD, highlights recent advances in BiTE immunotherapies at AACR19.
Pablo Umaña, PhD, highlights recent advances in BiTE immunotherapies.

Umaña also showcased BiTEs being used to treat solid tumors, specifically one that targets the CEA marker that is overexpressed in a variety of solid cancers. By fine tuning its affinity-avidity profile, this BiTE was designed to only target cancer cells that express high levels of CEA, thus potentially avoiding side effects as a result of targeting healthy cells that express lower levels of CEA. In mice, this CEA-targeting BiTE induced T cell infiltration into tumors and tumor cell death within 24 hours and was associated with rapid upregulation of PD-1 and PD-L1 expression. Consequently, superior anti-tumor activity was observed when this BiTE was combined with PD-L1 immunotherapy. In the clinic, this BiTe has already demonstrated encouraging activity—both alone and in combination with PD-L1—in patients with heavily-pretreated, microsatellite stable (MSS) colorectal cancer.

Lastly, Umaña spoke about a BiTE that targets the FAP marker expressed by cancer-associated stromal cells as well as the 4-1bb receptor that acts as a co-stimulatory switch on T cells. This BiTE was shown to synergize with the above CEA-targeting BiTE in a mouse model of stomach cancer and also demonstrated the ability to target tumors and lymph nodes in monkeys with colorectal cancer. Preliminary clinical results also revealed initial signs of activity in patients associated with increased T cell infiltration into tumors.

Following Umaña was Judith Varner, PhD, of the University of California, San Diego, who discussed a strategy to target the macrophages that control adaptive immune responses within tumors. Given that higher proportions of macrophages within tumors are associated with tumor progression, Varner sought to target the PI3Kγ signaling pathway that is required for their recruitment. After showing that PI3Kγ depletion inhibited macrophage recruitment and tumor growth in mice, she revealed that a first-in-class PI3Kγ inhibitor was able to shift macrophage activity from immune-suppressing to immune-stimulating, which led to the recruitment and activation of killer T cells. This approach also synergized with PD-1 checkpoint immunotherapy to increase survival in an HPV-positive head and neck cancer model in mice while at the same time promoting the development of persistent immune memory. In a phase I/Ib trial, by itself this PI3Kγ inhibitor reduced the number of immunosuppressive myeloid cells in circulation and increased the proliferation of exhausted T cells. When given in combination with PD-1 immunotherapy, it increased the expression of the T cell-recruiting cytokines CXCL9 and CXCL10.

Judith Varner, PhD, discusses a strategy to target the macrophages at AACR19.
Judith Varner, PhD, discusses a strategy to target macrophages.

The following session was chaired by Robert D. Schreiber, PhD an assistant director of the CRI Scientific Advisory Council whose lab at the Washington University School of Medicine in St. Louis has been funded by CRI throughout the last twenty years. CD8+ killer T cells—which recognize and target mutated tumor neoantigens in the context of MHC class I molecules—receive most of the attention in cancer immunotherapy, given their well-documented ability to directly eliminate cancer cells. However, Schreiber highlighted exciting new results out of his lab that revealed that CD4+ helper T cells—which recognize and target mutated tumor neoantigens in the context of MHC class II molecules—are important when it comes to eliminating tumors, too, showing that they promote the priming and activation of CD8+ killer T cells against MHC I-restricted neoantigens.

Robert D. Schreiber, PhD, discusses how CD4+ helper T cells promote the priming and activation of CD8+ killer T cells at AACR19.
Robert D. Schreiber, PhD, discusses how CD4+ helper T cells promote the priming and activation of CD8+ killer T cells.

To do so, Schreiber used a non-immunogenic mouse sarcoma cell line that doesn’t provoke immune responses against it and is resistant to combined PD-1 and CTLA-4 checkpoint immunotherapy. When he engineered these non-immunogenic tumors to express a mutated, MHC I-restricted neoantigen, it wasn’t enough to make these mice respond to combination immunotherapy. However, when he engineered it to express both an MHC I-restricted neoantigen and an MHC II-restricted neoantigen, the tumors grew more slowly without any treatment and were eradicated when the mice were treated with combination immunotherapy. Additionally, when mice were vaccinated with irradiated tumor cells, only those mice vaccinated with tumor cells containing both the MHC I- and MHC II-restricted neoantigens were successfully able to protect themselves when they were later re-challenged with tumors. In effect, the mutated MHC II-restricted neoantigen enhanced the generation of CD8+ killer T cells against the MHC I-restricted neoantigen.

Lastly, and perhaps most surprisingly of all, Schreiber demonstrated in an ingenious experiment that successful anti-tumor immune responses depended on the physical presence of these CD4+ T cells within tumors. When mice were transplanted with two tumors—one with both the MHC I- and MHC II-restricted neoantigens, and one with only the MHC I-restricted neoantigen—on different sides of their bodies, only tumors with both neoantigens were eliminated. Unsurprisingly, these tumors were associated with enhanced accumulation of both CD4+ helper T cells and CD8+ killer T cells compared to the tumors with only the one neoantigen.

Later in that session, UCLA’s Antoni Ribas, MD, PhD, a member of the CRI Clinical Accelerator Leadership, highlighted work—some of which was funded by through the SU2C-CRI Immunology Dream Team grant—that explored combination strategies to overcome resistance to PD-1 immunotherapy. Ribas began by discussing the mechanisms of resistance that can occur, including primary resistance due to low immunogenicity, low interferon gamma (IFNγ) signaling, or T cells being excluded from tumors as well as acquired resistance that can result from loss-of-function mutations that knock out tumors’ antigen presentation machinery or their IFNγ signaling activity.

Antoni Ribas, MD, PhD, explores combination strategies to overcome resistance to PD-1 immunotherapy at AACR19.
Antoni Ribas, MD, PhD, explores combination strategies to overcome resistance to PD-1 immunotherapy.

While defects in IFN signaling (both type I and type II) led to resistance to adoptive cell therapy (ACT), due to the lack of MHC I expression, Ribas revealed a factor that, when overexpressed, was able to bypass this requirement for MHC I expression, reversing this resistance and restoring sensitivity to ACT. Next, Ribas turned to treatments that activate the TLR9 pathway, showing that when given in combination with PD-1 therapy it could induce clinical responses in patients who possessed IFNγ pathway defects and didn’t respond to prior PD-1 therapy. A therapeutic preparation of double-stranded RNA, known as BO112, in combination with PD-1 therapy, was also able to induce responses in previously PD-1-refractory patients. Ribas also highlighted the combination of PD-1 therapy plus the oncolytic virus T-VEC, which led to high response rates in patients regardless of whether or not their tumors has already been recognized and infiltrated by CD8+ killer T cells. This approach is currently being evaluated in patients who didn’t respond to PD-1 therapy alone. NKTR-214, which activates the interleukin-2 (IL-2) receptor pathway, also synergized with PD-1 therapy as a first-line treatment in patients with metastatic melanoma, leading to responses in 62% of PD-L1-positive patients and 42% of PD-L1-negative patients. Lastly, Ribas highlighted a factor that his lab recently identified whose expression was enriched in tumors with poor T cell infiltration. When this factor, which activates β-catenin and the MYC signaling programs, was knocked out it reversed PD-1 resistance in a mouse model of melanoma in a CD8+ T cell-dependent fashion.

While metabolism plays an important role in fueling cancer’s growth, it also appears to be important when it comes to cancer cells’ ability to repair themselves and maintain their immortality, according to CRI CLIP Investigator Stephen J. Kron, MD, PhD, of the University of Chicago, who explored how we might be able to “shut off its fountain of youth.” As Kron noted, radiation induces DNA double-strand breaks (DSBs) in cancer cells, which results in the formation of nodules called foci. A number of molecules, including PARP, are then involved in resolving these foci and repairing the DSBs. PARP inhibitors, Kron showed, can block this foci resolution and inhibit DSB repair. When PARP inhibition was combined with radiation, it resulted in persistent foci and unrepaired DSBs, and led to large, flat cells that remained metabolically active but also exhibited signs of senescence (or age-related exhaustion and deterioration), including the secretion of inflammatory cytokines. Kron also found that this combination was more effective at slowing tumor growth in mice with intact immune systems, suggesting that this senescent state might be immunogenic.

Stephen J. Kron, MD, PhD, discusses how to stop cancer cells’ ability to repair themselves and maintain their immortality at AACR19.
Stephen J. Kron, MD, PhD, discusses how to stop cancer cells’ ability to repair themselves and maintain their immortality.

Interestingly, when gylycolytic enzymes involved in glucose metabolism were knocked out, this accelerated cellular senescence, while their overexpression blocked senescence. Cancer cells exposed to low glucose levels had enhanced persistence of foci and experienced accelerated senescence. Digging deeper, Kron identified glycosylation—or the process through which cells add sugars onto other molecules, especially proteins—as the culprit. Specifically, he determined that N-acetylglucosamine (also known as GlcNAc) played an important role, as its addition to cell cultures improved foci resolution and modulated radiation resistance. One of the enzymes responsible for the production of GlcNAc was also shown to promote DSB repair and survival and blocks senescence in cells exposed to radiation. When it was blocked, it restored the sensitivity of tumors to radiation as well as PARP inhibition.

Another potential strategy to support anti-tumor immune responses against hard-to-treat cancers was presented by Kevin M. Sullivan, PhD, a CRI-Fibrolamellar Cancer Foundation fellow at the University of Washington. Sullivan focused on interleukin-10 (IL-10), which is a key mediator of immunosuppression in the liver. When the IL-10 pathway was blocked, it reactivated anti-tumor immune responses against colorectal cancer liver metastases in mice and resulted in increased tumor apoptosis after expansion and activation of CD8+ killer T cells.

Finally, Cornelis J. M. ‘Kees’ Melief, MD, PhD, a former CRI grantee and a member of the CRI Scientific Advisory Council, delivered the 2019 Lloyd J. Old Award in Cancer Immunology lecture. During this talk, Melief highlighted a number of breakthroughs made in his lab over the last few decades that helped advance virus-targeting vaccine strategies against cancer. These included showing: the effectiveness of a human papilloma virus (HPV)-targeting vaccine in mice with HPV-positive cancer; that CD4+ helper T cells aid CD8+ killer T cells via the CD40 pathway; that long peptides worked better than short peptides and proteins when it comes to stimulating vaccine-induced immune responses; that HPV+ tumor eradication is dependent on the choice of an appropriate immune adjuvant; that vaccine-induced memory CD8+ T cell responses predict therapeutic effectiveness; and that these HPV-targeting vaccines synergized with low-dose, non-toxic chemotherapy treatment that depleted immunosuppressive myeloid cells.

Cornelis J. M. ‘Kees’ Melief, MD, PhD, delivers the 2019 Lloyd J. Old Award in Cancer Immunology Lecture at AACR19.
Cornelis J. M. ‘Kees’ Melief, MD, PhD, delivers the 2019 Lloyd J. Old Award in Cancer Immunology Lecture.

These preclinical breakthroughs paved the way for the application of HPV-targeting vaccines for human patients, which have proven clinically beneficial for patients with premalignant vulvar intraepithelial neoplasia (VIN3) as well as for patients with HPV-positive head and neck cancer in combination with PD-1 immunotherapy.

Early results from one of Melief’s ongoing trials also revealed the potential benefits of HPV-targeting vaccination in combination with chemotherapy in patients with advanced cervical cancer. Looking to the future, Melief also highlighted a planned phase III trial that will combine chemotherapy, PD-1 immunotherapy, and HPV-targeting vaccines. For more on Melief and his work, be sure to read the recent interview he gave to CRI.

Drs. Jill O-Donnell-Tormey, Cornelis Melief, and Ellen Pure at LJO Award Lecture (AACR19).
Drs. Jill O’Donnell-Tormey, Cornelis Melief, and Ellen Puré. 

That’s it for Day 5 from AACR19! Be sure to check back on our blog in the coming days for our final day and overall recap of AACR19.

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