Full Press Release Details
Lion Biotechnologies, Inc. is an emerging
biotechnology company focused on developing and commercializing adoptive cell therapy (ACT) using autologous tumor infiltrating
lymphocytes (TIL) for the treatment of metastatic melanoma and other solid cancers. ACT using TIL was developed by Dr.
Steven Rosenberg, Chief of Surgery at the National Cancer Institute (NCI), who is a recognized pioneer in immuno-oncology. ACT
utilizes the patient's own immune system (T-cells harvested from a patient) to treat cancer in that patient. TIL
are anti-tumor T-cells that are naturally present in a patient's tumors and are collected from individual patients'
tumor samples. The TIL are then activated and expanded ex vivo and then infused back into the patient to eliminate tumor
Adoptive cell therapy using tumor infiltrating lymphocytes
Patients undergoing TIL therapy
must have their tumors surgically resected. The TIL are then isolated, activated, and expanded to billions in vitro, away
from cancer's immune-suppressing effects. These highly activated, potent TIL are then infused back into the patient, who
has been preconditioned to remove all suppressive influences.
Our lead product candidate, TIL
for the treatment of melanoma, is based on the clinical development and trials conducted by Dr. Steven A. Rosenberg at the
NCI. For more than a decade, clinical development and trials have been conducted by the NCI, MD Anderson Cancer Center
(MD Anderson), the H. Lee Moffitt Cancer & Research Institute (Moffitt) and Sheba Hospital in Israel. We are also aware
of other on-going clinical trials, including on-going work by other non-profit institutions, hospitals and academic
institutions in the U.S. and Europe. Although we are funding development of TIL at NCI and work closely with some of the
physicians involved in developing these technologies at Moffitt and MD Anderson, to date we have not been the sponsors
of these clinical trials. Our goal is to initially focus on metastatic melanoma, but to also expand the development of
TIL therapy to treat other solid tumors. Results from Phase 1 and Phase 2 clinical trials conducted in small patient
populations at these four institutions show that between 46% and 49% of stage IV metastatic melanoma patients refractory to
other treatments and treated with TIL experienced an objective response, showing greater than 50% tumor shrinkage. Complete
responses, where all of the tumor was eradicated, occurred between 7% and 13% of patients. Of 20 refractory metastatic
melanoma patients treated with TIL therapy at the NCI who had complete responses, 19 are ongoing from seven to more than ten
years. The graph below shows the long term survival of this 93 patient NCI study showing more than 25% long term survivors
In a recent two-arm randomized trial of 101 patients at the
NCI to determine the effect of improved lymphodepletion on the clinical outcomes, an objective response rate of 54% was achieved.
There were 14 complete responders, 13 of which are ongoing beyond two years. Of the 41 partial responders, 22 are ongoing beyond
a year and 15 ongoing beyond two years.
TIL therapy in patients with metastatic
melanoma have durable responses with high complete response rates relative to CTLA-4 antibodies, such as ipilimumab (Yervoy), BRAF
inhibitors, such as vemurafenib (Zelboraf), PD-1/PD-L1 antibodies, such as nivolumab (Opdivo) or lambrolizumab (Keytruda), interleukin
2 (IL-2), and anti-cancer chemotherapy drugs such as dacarbazine (DTIC). The following chart summarizes the response rates relative
to other treatment options.
(The data summary above compares various treatments used for
melanoma at various stages and is a summary overview based on various published results. Some of these products may have higher
or lower response rates in other studies. These comparisons are not based on head-to-head randomized trials rather historical data
only. The patients selected in these trials vary from 1st line to 2nd or 3rd line and, therefore,
the foregoing chart should be used for illustrative purposes only, and not as a direct comparison.)
Intellectual Property
Under a patent license agreement (the NIH
License Agreement) with the National Institutes of Health (NIH), an agency of the United States Public Health Service within the
Department of Health and Human Services, we have acquired a non-exclusive, worldwide right and license to develop and manufacture
autologous TIL for the treatment of metastatic melanoma, ovarian, breast and colorectal cancers. The intellectual property subject
to the NIH License Agreement is covered by patents and patent applications, consisting of issued and pending patent applications
in the United States, as well as foreign patents and pending patent applications as counterparts of U.S. patents and patent applications,
including Europe, Australia, and Canada. The NIH License Agreement will expire on a product-by-product basis upon the expiration
of the subject patent rights. The subject matter claimed in the patents and patent applications that were licensed by us under
the NIH License Agreement generally relates to:
We recently surrendered to the NIH some
of the unnecessary patents/patent applications included in the NIH License Agreement. The patents and patent applications currently
covered by the NIH License Agreement include non-exclusive licenses to (i) adoptive immunotherapy with enhanced T lymphocyte survival
(using T lymphocytes genetically modified to express IL-15) (issued U.S. patent no. 7,998,736), (ii) immunotherapy
with in vitro-selected antigen-specific lymphocytes after non-myeloablative lymphodepleting chemotherapy (issued U.S. patent nos.
8,034,334 and 8,287,857), (iii) methods of growing TIL in gas-permeable containers (pending), and (iv) adoptive cell therapy with
young T-cells (issued U.S. patent no. 8,383,099 and a pending U.S. continuation application). We also have the right to issued
patents, or patent applications, for certain of the issued patents filed in Australia, Canada, and Europe. The issued U.S. patents
will expire at various times through 2030, assuming that all maintenance fees are timely paid. We have conducted freedom-to-operate
analyses of the current patent landscape with respect to our lead product candidate, and based on these analyses we believe that
we have the freedom to operate for metastatic melanoma. However, the area of patent and other intellectual property rights in biotechnology
is an evolving one with many risks and uncertainties.
On July 21, 2014, we entered into an exclusive
license agreement with Moffitt (Moffitt License Agreement) under which we received an exclusive, worldwide license to Moffitt's
rights in and to two technologies. For each of the technologies covered under the Moffitt License Agreement, there is a U.S. provisional
application pending, which technologies are related to methods for improving tumor-infiltrating lymphocytes for adoptive cell therapy.
The license covers the application of this technology to metastatic melanoma and other solid tumor types, including triple-negative
breast cancer, non-small cell lung cancer and other tumors that historically have been difficult to treat. However, no assurance
can be given that any patent will issue in the United States or any other country from these licensed patent applications.
Currently, we are also in discussions with
the NIH to license additional exclusive rights to genetic engineering of T-cells. These next generation T-cell technologies include
designer T-cells to incorporate cytokines to enhance activity and checkpoint inhibition to control the tumor microenvironment.
Next generation T-cell technologies include TIL enriched for higher potency that have a lower cost of goods and a shorter manufacturing
process. However, no assurance can be given that we will be able to license these additional rights, or that any patent will issue
in the United States or in any other country from any of such additional licensed patent applications.
In 2011 we entered into a Cooperative Research
and Development Agreement (CRADA) with the NCI, pursuant to which we support the in vitro development of improved methods
for the generation and selection of TIL, develop approaches for large-scale production of TIL, and conduct clinical trials using
these improved methods of generating TIL for the treatment of metastatic melanoma. The CRADA provides that we are entitled to obtain
exclusive rights to the technologies developed thereunder. We have elected to exercise our option to negotiate an exclusive license
to new adoptive cell therapy technologies for the treatment of metastatic melanoma. However, no assurance can be given that we
will receive these rights from the NCI. The CRADA also provides us with access to important clinical data, manufacturing data and
to operating procedures.
TIL therapy to date has been limited
because manufacturing of TIL is currently labor intensive, costly, and time-consuming. We have entered into a Manufacturing Services
Agreement with Lonza Walkersville, Inc. (Lonza) pursuant to which Lonza has agreed to manufacture, package, ship and handle quality
assurance and quality control of our TIL. Lonza has commenced developing a commercial-scale manufacturing process for the TIL therapy.
Our goal is to develop and establish a manufacturing process for the large-scale production of TIL that is in accord with current
Good Manufacturing Practices (cGMP). By providing centralized manufacturing, we believe TIL therapy can be made more widely available
to a larger number of cancer patients. Since 2011 we have worked with NCI to develop new systems for large scale manufacturing
of TIL and to transfer the manufacturing process to Lonza for further development. The following diagram illustrates our proposed
TIL manufacturing process.
Development Plans and Goals
In addition, the NCI, under our CRADA, is
currently continuing to test TIL in metastatic melanoma patients either alone, or in combination with other therapeutic agents.
We intend to supplement the research being conducted under the CRADA with research to be conducted at our research facility recently
established in Tampa, Florida, near Moffitt on the campus of the University of South Florida, and through a clinical trial grant
agreement we entered into with Moffitt in July 2014 to expand an ongoing Phase 1 study of TIL combined with the checkpoint inhibitor
ipilimumab in patients with metastatic melanoma.
We plan to file an investigational new