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In previous years, delegates at the American Society for Clinical Oncology (ASCO) annual meeting had been treated to exciting clinical data from anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies such as Kymriah (tisagenlecleucel; Novartis), Yescarta (axicabtagene ciloleucel; Gilead), and various pipeline assets in advanced hematologic malignancies. While these now form part of the standard of care for acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), respectively, attention is switching towards different CAR-T constructs and other cell therapy approaches that may show promise in solid tumors, which have so far proven elusive. Over 90% of cancers arise from solid organs, so solving this problem will be essential for cell therapy to become a mainstream treatment modality. With this in mind, we will review some of the latest approaches coming under the spotlight at ASCO 2019 to tackling solid tumors via cell therapies, including tumor-infiltrating lymphocytes (TILs) and novel CAR-T antigens.

Tumor-infiltrating lymphocytes show the greatest promise for a range of solid tumors

Speaking at the end of ASCO on a Tuesday morning when most were flying out of Chicago, Dr Christopher Klebanoff of Memorial Sloan Kettering Cancer Center was reviewing the latest in oncology cell therapy to emerge from the meeting. When it comes to solid tumors, while individual CAR-T therapies are starting to show proof of concept in defined patient populations, the best evidence continues to come from adoptive cell therapy using TILs, based on the research of the National Cancer Institute (NCI) and Iovance Biotherapeutics. TILs are part of the natural anti-cancer machinery, able to recognize many different neoantigens expressed by tumor cells, and migrate throughout the body, even crossing the blood-brain barrier. TIL therapy, which has been refined over a period of three decades, entails harvesting TILs from a tumor biopsy, then expanding ex vivo in the presence of cytokines, before cells with the most potent anti-tumor activity are reinfused. Unlike CAR-T manufacture, there is no genetic engineering of the cell therapy, as described in the graphic below.

Tumor-infiltrating lymphocyte therapy process

Car-t therapies

 


 
Source: Datamonitor Healthcare

Historically, adoptive cell transfer of TILs has been mainly evaluated in metastatic melanoma patients. Dr Stephanie Goff of the NCI shared data first published in 2011 among 194 such patients who have exhausted all prior therapies [1]. An overall response was seen in 107 patients (56%), including 46 complete responses (24%). For those patients that achieve a complete response, TIL appears capable of eliminating the last cancer cell. Only two such patients have died with up to 12 years of follow-up, pointing towards TIL as a remarkable curative treatment option in this setting. TILs have also been shown to mediate complete regression among metastatic breast cancer patients, with partial responses also noted in gastrointestinal cancers.

With such a strong proof of concept now established, Iovance Biotherapeutics is one of the leading companies pioneering the commercialization of this approach, and it has partnered with the NCI for the technology. Iovance’s proprietary manufacturing approach enables the production and infusion of 109–1011 TILs within 22 days of biopsy, and the company has invested in a 136,000 sq ft facility to enable GMP production on the scale required to treat a number of different solid tumors by 2022 [2]. While having the infrastructure to deliver cell therapies on this scale is one challenge, Iovance also needs to generate its own supportive clinical data ahead of potential first regulatory filings in 2020.

On this front, Iovance attracted a lot of attention at ASCO for its presentations supporting Contego (lifileucel; LN-144) in melanoma (Abstract 2518) and LN-145 in cervical carcinoma (Abstract 2538). For melanoma, Iovance released data for 66 patients in cohort 2 of its innovaTIL-01 trial, showing a 38% objective response rate, 80% disease control rate and median duration of response not reached with an 8.8-month follow-up. In cervical carcinoma, LN-145 similarly achieved a 44% objective response rate and 85% disease control rate after 7.4 months of patient follow-up in the innovaTIL-04 study. While the data are not as remarkable as previously reported by the NCI, they are very promising for Iovance’s prospects of reaching the market in such heavily pre-treated patients. Both programs have been awarded fast track status and breakthrough therapy designation at the US Food and Drug Administration (FDA), and Iovance expects to file Contego for approval in H2 2020 upon the completion of cohort 4 of innovaTIL-01.

Iovance’s tumor-infiltrating lymphocyte clinical data at ASCO


 

Contego in melanoma

LN-145 in cervical carcinoma

Number of evaluable patients

66

27

Objective response rate

38%

44%

Disease control rate

80%

85%

Complete responses

Two patients

Three patients

Partial response

23 patients

Nine patients

Median duration of response

n/a

n/a

Median follow-up

8.8 months

7.4 months

Source: Biomedtracker

With the clinical and regulatory work being conducted in tandem by academia and industry, it looks likely that TIL therapy will become the latest immuno-oncology approach to reach patients. New proof-of-concept trials are under way across a range of treatment settings, meaning that TIL may also have large-scale application. Achieving this scale may be important if TIL is to be a commercially viable proposition for companies such as Iovance, avoiding some of the pitfalls that Dendreon faced in its marketing of Provenge (sipuleucel-T). The total cost of TIL will also need to be carefully considered, taking into account the high incidence of solid tumors and subsequent development work in combination trials with expensive checkpoint inhibitors.

Mesothelin-directed CAR-T cells show potential in pleural cancers and beyond

While TILs stole the cell therapy show at ASCO, several other groups were sharing research for new CAR-T designs in well-defined subgroups of patients with solid tumors that have failed previous conventional therapies. The challenge is selecting an appropriate antigen that is essential for tumor growth, with universal expression on the surface of tumor cells and limited expression in normal tissues, to limit toxicity. Among the new CAR-Ts discussed were programs against Claudin 18.2 and B7-H3, while CEA, HER2, and GD2 are also widely studied, but perhaps the target with the broadest therapeutic potential in solid tumors is mesothelin. Mesothelin is a cell-surface antigen expressed in the majority of solid tumors, including 85–90% of mesotheliomas, with an estimated annual incidence and prevalence of 340,000 and 2 million patients, respectively, in the US alone [3]. To date, no drugs against mesothelin – small molecule, biologic, or otherwise – have progressed to Phase III trials or beyond, although the CAR-T modality is now showing clinical promise.

Atara Biotherapeutics and collaborators at Memorial Sloan Kettering Cancer Center announced results from a trial of 27 patients with advanced pleural cancers, evaluating an anti-mesothelin CAR-T construct using a novel 1XX signaling domain and PD-1 dominant negative receptor (Abstract 2511). As shown in the table below, the results for 16 evaluable patients with mesothelioma are highly encouraging, with a 63% response rate including three complete responses. Furthermore, there was little association with cytokine release syndrome or neurotoxicity, which are limiting side effects noted with currently approved CD19-targeted CAR-T therapies.

Phase I study of anti-mesothelin CAR-T in advanced mesothelioma

Measure

Result

Number of patients

27

Number of evaluable mesothelioma patients

16

12-month overall survival

80%

Best overall response rate

63%

Investigator-assessed complete responses

Three patients

Partial responses

Seven patients


Source: Biomedtracker

The trial also confirmed the benefits of combining the CAR-T and anti-PD-1 approaches in mesothelin-expressing cancers. It was shown that the effectiveness of the CAR-T therapy alone was potentiated by an increase in PD-L1 expression on tumor cells as a result of treatment. Thus, the administration of the mesothelin-targeted CAR-T treatment seemed to prime the tumor to be treated more effectively by anti-PD-1 therapy, while the administration of a PD-1 inhibitor also seemed to prolong the effect of the previously administered CAR-T cells.

Atara is expected to initiate subsequent development of this CAR-T candidate in mesothelioma, with the possibility that the company could move directly into a registration-enabling study that would allow for accelerated approval. Considering the expression of mesothelin across various tumor types, a broader development program would also have large commercial appeal. Atara is likely to face competition from other companies seeking to develop mesothelin-targeting drugs. As shown in the table below, there are 13 separate clinical programs featuring a number of drug and tumor types.

Clinical-stage pipeline for mesothelin-targeting drugs in oncology

 

Drug

Company

Mechanism

Indications

Highest phase

amatuximab

Eisai

Mesothelin MAb

Mesothelioma

Phase II

anetumab ravtansine

Bayer

Mesothelin ADC

Unspecified solid tumors

Phase II

BMS-986148

Bristol-Myers Squibb

Mesothelin ADC

Unspecified solid tumors

Phase II

HPN-536

Harpoon Therapeutics

Trivalent polypeptide binding mesothelin, HSA, and CD3

Ovarian, pancreatic, and solid cancers

Phase II

n/a

Shenzhen BinDeBio

Mesothelin CAR-T

Pancreatic cancer

Phase II

TC-210

TCR2 Therapeutics

Mesothelin TCR

Mesothelioma, biliary, ovarian, and non-small cell lung cancer

Phase II

ABBV-428

AbbVie

CD40/mesothelin bispecific antibody

Unspecified solid tumors

Phase I

ATA2271

Atara Biotherapeutics

Mesothelin CAR-T

Unspecified solid tumors

Phase I

BAY-2287411

Bayer

Mesothelin ADC

Mesothelioma, ovarian cancer

Phase I

MCY-M11

MaxCyte

Mesothelin CAR-T

Mesothelioma, ovarian cancer

Phase I

n/a

Hebei Senlang Biotechnology

Mesothelin CAR-T

Mesothelioma, pancreatic, and ovarian cancer

Phase I

n/a

Novartis

Mesothelin CAR-T

Mesothelioma, pancreatic, and ovarian cancer

Phase I

n/a

Shanghai Unicar-Therapy Biomed

Mesothelin CAR-T

Pancreatic cancer

Phase I

ADC = antibody-drug conjugate; CAR-T = chimeric antigen receptor T-cells; HSA = human serum albumin; MAb = monoclonal antibody; TCR = T-cell receptor


Source: Pharmaprojects


References

[1] Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, et al. (2011) Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clinical Cancer Research, 17(13), 4550–57. Available from: 10.1158/1078-0432.CCR-11-0116 [Accessed June 24, 2019].
[2] Iovance Biotherapeutics (2019) Investor Presentation. Available from: http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9NzA3MTc0fENoaWxkSUQ9NDIwMDYyfFR5cGU9MQ==&t=1 [Accessed June 24, 2019].
[3] Morello A, Sadelain M, Adusumilli PS (2016) Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discovery, 6(2), 133–46. Available from: 10.1158/2159-8290.CD-15-0583 [Accessed June 24, 2019].

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