Late stage cellular immunotherapy products for treatment of hematologic tumors

In the field of commercialization of cellular immunotherapy for cancer, all eyes have been on two chimeric antigen receptor (CAR) T-cell therapies (from Novartis and Kite Pharma), which have been in preregistration with the FDA as of March 2017. We discussed the field of CAR-T cell therapies—as well as other cellular immunotherapies for cancer—in Chapter 6 of our recently published book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes

Both the Novartis therapy, CTL019 (tisagenlecleucel-T), and the Kite therapy, KTE-C19 (axicabtagene ciloleucel) target CD19, which is a cell surface protein that is expressed on all malignant and normal B-cells.

On July 13, 2017, Novartis announced  that FDA’s Oncologic Drugs Advisory Committee (ODAC) had unanimously recommended approval of CTL019 for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). The ODAC recommendation is based on review of Novartis’ CTL019 r/r B-cell ALL development program, including the ELIANA study (NCT02435849). ELIANA is the first pediatric global CAR-T cell therapy registration trial. Findings from other clinical trials in the U.S. also supported the recommendation and the Biologics License Application (BLA) for CTL019.

On August 30, 2017 the FDA approved Novartis’ CTL019—now known as Kymriah (tisagenlecleucel)—for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Novartis’ Kymriah is thus the first-ever commercially approved CAR-T cell therapy to reach the market. However, Kite’s KTE-C19 is close on Novartis’ heels.

On August 28, 2017, Kite and Gilead announced that the two companies have entered into a definitive agreement pursuant to which Gilead will acquire Kite for $11.9 billion. Via this acquisition, Gilead “instantly” becomes a leader in cellular immunotherapy for cancer, going head-to-head with Novartis.

On October 18, 2017, Kite and Gilead announced that the FDA had approved Kite’s Yescarta (axicabtagene ciloleucel, also known as axi-cel), for the treatment of adults with relapsed or refractory large B-cell lymphoma, including aggressive non-Hodgkin lymphoma, who have failed two or more traditional treatments. Yescarta was approved about six weeks earlier than expected.

Other CAR-T based immunotherapies for treatment of hematologic tumors

As discussed in our report, there is also a third company, Juno Therapeutics, that was in the race to develop CD19-targeting CAR-T-based cellular immunotherapies for regulatory approval in 2017. However, Juno’s lead product, JCAR015, suffered a series of toxicity-related setbacks. Juno thus abandoned both JCAR015 and the race for 2017 approval. It is now focusing on development of another CD19-targeting CAR-T product, JCAR017. This therapy is directed towards treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

JCAR017 demonstrated promising efficacy results in a Phase 1 trial known as TRANSCEND. Adverse results were generally mild, and could be resolved with treatment. [ The company presented the results of the TRANSCEND trial at the 2017 American Society for Clinical Oncology (ASCO) annual meeting in early June.]

Juno expects to begin a pivotal trial of JCAR017 this year in DLBCL. JCAR017 received a breakthrough therapy designation from the FDA for non-Hodgkin lymphoma in December 2016.

As we also discuss in our report, another CAR-T therapy directed against a hematologic malignancy, bluebird bio’s bb2121, is under development in collaboration with Celgene. bb2121 targets B-cell maturation antigen (BCMA), and is directed toward treatment of multiple myeloma (MM). bluebird and Celgene announced the results of an ongoing first-in-human open-label Phase 1 multicenter clinical study of bb2121 in 18 patients with relapsed/refractory MM at the 2017 ASCO Annual Meeting on June 5, 2017. bb2121 demonstrated promising efficacy results in this study, and no dose-limiting toxicities were observed. No patient in the active dose cohorts has had disease progression. The researchers thus plan on initiating the expansion phase of the study in the coming months of 2017.

Can researchers develop cellular immunotherapy for solid tumors?

As various companies work to move CAR T-cell therapies that target tumor antigens other than CD19 into the clinic, a particularly important question is whether CAR T-cell technology might be used to target solid tumors. Our report  discusses several clinical-stage products designed to target various types of solid tumors. These include products in three categories—tumor-infiltrating lymphocytes (TILs), CAR T-cells, and recombinant T-cell receptor (TCR) cells. Researchers developing such therapies (especially CAR T-cell therapies) recognize the special difficulty in targeting solid tumors, and are including studies attempting to determine the barriers that might prevent effective therapy of solid tumors with their experimental therapies. Some companies have also been producing therapies that are designed to overcome these barriers.

Now comes a “Brief Report” (published in December 2016) in the New England Journal of Medicine that focuses on an experimental treatment for the brain cancer glioblastoma with CAR T-cells. The study was carried out by researchers at the City of Hope (Duarte, CA). In this study, the CAR T-cells used were designed to target the high-affinity interleukin-13 (IL-13) receptor IL13Rα2, which is overexpressed in a majority of glioblastomas. The researchers administered the therapy locally in the brain, by injecting it into the tumor site and/or via infusion in the brain’s ventricular system. This contrasts with the use of CAR T-cells for treatment of hematological malignancies, in which the CAR T-cells are administered systemically.

Treatment with the CAR T-cells induced a transient, complete response in a patient with recurrent multifocal glioblastoma. This included a dramatic improvement in quality of life, including the discontinuation of use of systemic glucocorticoids and a return to normal life activities. The remission was sustained for 7.5 months. Nevertheless, the patient eventually developed new tumors. The authors concluded that their study provides proof-of-principle data that confirm IL13Rα2 as a useful immunotherapeutic target in glioblastoma, and suggest that CAR T cells can mediate profound antitumor activity against a difficult-to-treat solid tumor.

Meanwhile, as discussed in our report, researchers at Kite Pharma and University of Pennsylvania/ Novartis have been studying treatment of glioblastoma with CAR T-cells that target the epidermal growth factor receptor variant III (EGFRvIII). Some 20-30% of glioblastomas express this variant. The two groups are running parallel early-stage clinical trials of two different EGFRvIII CAR agents. The researchers believe that these parallel studies may be informative for future development of CAR therapies for solid tumors. However, no dramatic results such as seen by the City of Hope group have yet been reported for these studies.

TIL therapies for solid tumor cancers

Currently, the most successful cellular immunotherapies for solid tumor cancers have involved treatment with TILs. Steven A. Rosenberg, M.D., Ph.D., of the National Cancer Institute pioneered the study of TIL therapy, and of cellular immunotherapy in general. Our 2017 report  includes extensive discussions of the studies of TIL therapy carried out by Dr. Rosenberg and his collaborators, from the 1980s to today. Unlike CAR T-cell and recombinant TCR-based therapies, TILs are normal T cells that have not been genetically engineered.

Most clinical studies with TIL therapy have been in advanced melanoma. However, more recent studies have included “proof of principle” studies in patients with epithelial cancers of the digestive system. In some cases, these have included studies with TILs that target cancers with the KRAS G12D mutation, a notorious “undruggable” driver mutation that is involved in causation of many human cancers. More recent work in Dr. Rosenberg’s group has included mechanistic studies designed to determine the neoantigens that are targeted by antitumor TILs. Some of these most recent studies are being applied to treatment of non-small cell lung cancer (NSCLC).

However, as discussed in our report and in another article on this blog , TIL therapies have been difficult to commercialize. Nevertheless, in recent years, a San Carlos, CA company called Lion Biotechnologies (which on June 27, 2017 changed its name to Iovance Biotherapeutics has been focusing on doing just that. Iovance has been working with Dr. Rosenberg and his colleagues at the NCI under a Cooperative Research and Development Agreement (CRADA) to develop and commercialize TIL therapies.

On June 5, 2017, Iovance announced a poster presentation  of a study of 16 patients enrolled in the first cohort of its ongoing Phase 2 study of LN-144 for the treatment of metastatic melanoma, at the ASCO Annual Meeting.   LN-144 is the company’s autologous TIL therapy for the treatment of patients with refractory metastatic melanoma. Iovance’s Phase 2 clinical trial of LN-144 (clinical trial number NCT02360579) is designed to assess the safety, efficacy, and feasibility of the autologous TIL therapy, followed by interleukin-2 (IL-2), in the treatment of this class of patients.

The data presented at the ASCO meeting showed that Iovance can manufacture TILs at its central GMP facilities to treat patients at multiple clinical sites. According to the company, the initial data show clinically-meaningful outcomes, as assessed both by objective response rate (ORR) and disease control rate (DCR), in a heavily pre-treated patient group, all of whom had received prior anti-PD-1 (e.g., pembrolizumab or nivolumab) and over 80% with prior anti-CTLA-4 (e.g., ipilimumab) checkpoint inhibitors.

In the ASCO poster presentation, the company’s academic collaborators presented updated data from 16 patients who were infused as of April 24, 2017. These advanced metastatic melanoma patients were a median age of 55 and were highly refractory to multiple prior lines of therapy with significant tumor burden at baseline. Of the evaluable patients, a 29% ORR was reported, including one complete response (CR) continuing beyond 15 months post-administration of a single TIL treatment. 77% percent of patients had reduction in target tumor size. The mean time to first response was 1.6 months, with the CR developing at 6 months.

Responses were observed in patients with wild type tumors and with tumors carrying BRAF  mutations. The protocol for this study was amended to increase the sample size for the study, as well as to further define the patient population to patients with unresectable or metastatic melanoma who have progressed after immune checkpoint inhibition therapy, and if BRAF mutation-positive, after BRAF targeted therapy.

In addition to the melanoma study, Iovance plans to initiate Phase 2 TIL therapy studies in cervical and head-and-neck cancers during 2017. The TIL populations to be used for these studies, LN-145, will be selected for reactivity to human papillomavirus (HPV) proteins E6 and E7. The selection and use of such TIL populations was developed by researchers in Dr. Rosenberg’s group. Iovance is currently enrolling patients in its Phase 2 melanoma and cervical and head-and-neck cancer studies.

Recent review on treating solid tumors with CAR-T cell therapies

Now comes a review by Irene Scarfò, Ph.D. and Marcela V. Maus, MD, Ph.D. published in March 2017 in the Journal for ImmunoTherapy of Cancer. This review focuses on factors that may limit the efficacy of CAR-T cell therapies in solid tumors, and how these factors might be overcome.

Some of the factors discussed in this review include:

• Hypoxia, nutrient starvation, and resulting changes in T-cell metabolism (many human solid tumors contain high percentages of hypoxic tissue)
• Interactions between CAR T-cells and tumor stroma that may inhibit the ability of CAR T-cells to penetrate tumors
• Targeting cytokine networks, for example by inducing the local release of cytokines that promote anti-tumor immune responses. For example, interleukin-12 (IL-12) is a key inflammatory cytokine, which is able to induce several pathways that promote such a response. (We discussed IL-12-based therapeutics for use in immuno-oncology, as well as therapeutics based on such cytokines as IL-2, IL-10 and IL-15, in Chapter 1 of our report.) Starting from these considerations, several groups are investigating so-called “fourth generation” CAR T-cells, which are CAR-T cells that are designed to secrete IL-12.

The immunosuppressive environment of the interior of solid tumors results in the upregulation of surface inhibitory receptors, especially programmed death-1 (PD-1) on CAR T-cells. PD-1 inhibits the antitumor activity of the CAR T-cells. Researchers are therefore developing therapies in which they treat solid tumors with a combination of CAR T-cells directed to an appropriate tumor antigen and an immune checkpoint inhibitor such as pembrolizumab or nivolumab. Alternatively, researchers may use a genetic engineering strategy to block PD-1.

Currently, researchers are testing approaches based on these factors in animal models, and may soon be advancing into human clinical trials. As with other approaches classified as “immuno-oncology 2.0”, these trials will involve the use of combination therapies. The goal of early clinical trials in this area will be to determine the safest and most effective combinations for treatment of patients with solid tumors.

Conclusions

The field of cellular immunotherapy for cancer is an increasingly exciting and fast-moving area. Most of the focus is on breakthrough treatments of CD19+ hematologic tumors, with late-stage CAR T-cell therapies such as Novartis’ CTL019 (tisagenlecleucel-T), and Kite’s KTE-C19 (axicabtagene ciloleucel), which are rapidly approaching the market. However, there are also new indications that researchers and companies might be able to develop cellular immunotherapy-based treatments for certain types of solid tumors in the next several years. All in all, cellular immunotherapy will be an increasing area of focus for researchers, companies, and analysts over the remainder of this decade and beyond.

For more information on our recent report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, or to order it, see the CHI Insight Pharma Reports website. 

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