Kate Venmar

Advancements in immuno-oncology have transformed cancer treatments in recent years. Clinicians will soon face challenging decisions on which immunotherapies to prescribe their patients, and in what sequence or combination. Fortunately, a variety of programs and conferences exists to promote the successful implementation of immunotherapy in the clinic.

Immunotherapies direct the body&rsquo;s own immune system to effectively attack cancer cells. Various immune approaches have been developed and tested to treat many cancer types, including adoptive T-cell transfer, vaccines, and pharmacologic immunotherapies such as checkpoint inhibitors.

Checkpoint inhibitors and cancer vaccines have been at the center of immunotherapy popularity after demonstrating durable responses in clinical trials.

Checkpoint inhibitors have been successful in targeting proteins that suppress immune function, such as programmed death-1 (PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4), thus allowing previously inactive immune cells to attack the tumors they infiltrate.

Cancer vaccines are appealing because they can prevent or treat cancer. However, the greatest success of checkpoint inhibitors or vaccines in the clinic may come when these therapies are delivered in combination. In fact, there are more than 19 ongoing clinical trials in melanoma alone focused on pairing immunotherapies or combining them with targeted therapies or cancer vaccines.

With so many possible immunotherapy combinations, how can oncologistswho now rely largely on surgery, radiation, and chemotherapy&mdash;effectively adopt their use in the clinic?

In fact, a plethora of resources exists for the education and training of clinical providers in immunology and immunotherapy, and more are in the pipeline. These include Targeted Healthcare Communications&rsquo; TargetedOnc.com, the Society for Immunotherapy of Cancer (SITC) programs, and the newly founded Institute for Clinical Immuno-Oncology (ICLIO). In addition, the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) are also planning major conferences on immunotherapy.

The Association of Community Cancer Centers (ACCC) has just received a charitable contribution from Bristol-Myers Squibb to establish the ICLIO, which will sponsor a comprehensive program to educate community-based providers about immuno-oncology and the appropriate implementation of immunotherapies across multiple tumor types in the clinic.

&ldquo;We are thrilled about the opportunity to help our members adopt innovations,&rdquo; stated Becky L. DeKay, MBA, president of ACCC. The comprehensive program will also be dedicated to assuring that patients who need them will have access to novel therapies. An advisory committee comprised of ACCC members and immuno-oncology leaders will oversee the development of ICLIO. The initial goal will be to establish the project infrastructure and identify partner organizations.

Eventually, ICLIO will use direction from community thought leaders, clinician scholars, and care providers to advance the scientific and clinical application of immunotherapies. Clinicians and fellows can look forward to an ICLIO national conference, a monthly e-course series, e-newsletters, and scientific and policy publications highlighting project findings and outcomes.

In the meantime, oncologists can go to Targetedonc.com to find free articles, videos, and continuing medical education (CME)-certified activities that explain the latest advances in immunotherapy options.

Targeted Healthcare Communications also publishes 2 print journals focusing on oncology therapeutics, with a particular focus on targeted therapies, biomarkers, and immunotherapies:

Targeted Therapies in Oncology&trade;, and

The Journal of Targeted Therapies in Cancer&trade;

Community-based providers can also visit Sitcancer.org to find support from the SITC, which is an international, nonprofit, medical professional society of researchers, clinicians, government representatives, and industry leaders. Its mission is to improve outcomes in patients with cancer through the development, advancement, and application of cancer immunology and immunotherapy.

&ldquo;There are a lot of immunotherapies in clinical trials, and we are gearing up to meet the demands of what&rsquo;s coming,&rdquo; said Kate Flynn, MPA, director of membership and outreach for SITC.

To meet these demands, SITC is offering regional

programs. These CME-certified programs are designed to provide cancer patient caregivers with the education and training they need regarding the principles and practice of immunotherapy in the clinic. They specifically address therapeutic effectiveness, clinical indications, and the appropriate selection of immunotherapies for cancer treatment, among other topics.

With so many possible immunotherapy combinations emerging, cancer care providers may have difficulty staying up-to-date on how to implement them effectively in the clinic. Fortunately, multiple resources exist to help educate and train clinicians in immunotherapy and the latest advancements in immuno-oncology. They include:

Society for Immunotherapy Cancer Research: Sitcancer.org

Websites with free online CME-certified programs

Websites with upcoming immunotherapy-based conferences

http://www/aacr.org/Meetings/Pages/EventListing.aspx#.VG1cDYfB_w4

http://www.asco.org/meetings/calendar-events

Future SITC projects include creating and updating guidelines for courses of US Food and Drug Administration (FDA)-approved immunotherapy treatment, and hosting an annual meeting. SITC&rsquo;s next annual meeting will take place November 5-8, 2015.

Moreover, there are multiple other conferences in the US with sessions focused on the clinical use of immunotherapies.

The AACR, in conjunction with its cancer immunology working group, plans to host a conference on December 1 of this year titled,

Tumor Immunology and Immunotherapy: A New Chapter

. ASCO is also planning to host several patient care and practice-centered sessions on immunotherapy in the clinic at its 2015 annual meeting starting May 29.

Koberstein W. Combination cancer immunotherapyA virtual roundtable. (Life Science Leader web site). September 2, 2014. http://lifescienceleader.com/doc/ combination-cancer-immunotherapy-0001. Accessed November 19, 2014.

Zhou J. Advances and prospects in cancer immunotherapy.

. 2014;2014:13 pages. Available at: http://www.hindawi.com/journals/njos/2014/745808/. Accessed November 19, 2014.

Shtivelman E. Immune system-activating drugs in combination treatments may be the next big thing for melanoma. (CancerCommons web site). October 20, 2014. http://www.cancercommons.org/2014/10/20/immune-system-activating-drugs-in-combination-treatments-may-be-next-big-thing-for-melanoma/. Accessed November 15, 2014.

Gardner L. ACCC to develop comprehensive program on immuno-oncology for community-based providers. (ACCC web site). October 21, 2014. http://www.accc-cancer.org/mediaroom/press_releases/2014/ACCC-to-Develop-Comprehensive-Immuno-Oncology-Program-for-Providers-10-21-14.asp. Accessed November 16, 2014

Gross M. Targeted Healthcare Communications launches website. [Targeted Oncology web site]. October 1, 2012. http://www.targetedonc.com/ resources/targeted-Healthcare-Communications-Launches-Website. Accessed November 19, 2014.

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Clinicians will soon face challenging decisions on which immunotherapies to prescribe their patients, and in what sequence or combination.

Programs Prepare for Immuno-Oncology in Clinical Setting

Several novel approaches to the delivery of therapeutics for advanced melanoma may improve treatment efficacy and patient survival. These approaches include injecting immunotherapies into the tumor, delivering individual immunotherapies in combination, and using nanoparticle carriers to enhance drug delivery.

Researchers and drug companies are currently investing heavily in immunotherapy treatments for melanoma. These agents are designed to induce or enhance an anticancer response in immune cells that commonly infiltrate melanomas, but don&rsquo;t usually attack the tumor.

Delivery of the talimogene laherparepvec (T-VEC) vaccine involves injecting the immunotherapy directly into the melanoma. When injected into the tumor, this oncolytic vaccine causes tumor membranes to rupture while triggering an anticancer immune response.

In September, Amgen, the company that produces T-VEC announced the submission of a marketing authorization application for the oncolytic vaccine to the European Medicines Agency as treatment for regional or distant melanoma metastases in adults. This submission &ldquo;brings us a step closer to helping address an unmet medical need for patients with metastatic melanoma,&rdquo; stated Sean Harper, MD, Amgen&rsquo;s chief of research and development.

While the pioneering approach of using therapeutic cancer vaccines has suffered setbacks in the clinical pipeline, delivering T-VEC directly into melanomas in combination with other therapeutic agents, including checkpoint inhibitors, may enhance efficacy.

Checkpoint inhibitors are pharmacologic immunotherapies that target immune suppressors such as PD-1 or CTLA-4. Inhibitors of PD-1 (Keytruda), or CTLA-4 (Yervoy), take the &ldquo;stop signal&rdquo; away from inactive immune cells, allowing them to attack cancer cells. Targeting &ldquo;PD-1 is truly a game-changer,&rdquo; said oncologist Lynn M. Schuchter, MD, in a statement to

Combining checkpoint inhibitors with oncolytic vaccines has the potential to elicit longer-lasting responses while limiting serious side effects. There are currently more than 19 ongoing clinical trials in melanoma patients pairing immunotherapy treatments with T-Vec, or targeted therapies such as the BRAF inhibitor, vemurafenib.

Importantly, the majority of these trials administer the therapies sequentially to limit toxicity.

In addition to delivering therapeutics in combination to improve efficacy, research is being done on delivering drugs to patients with nanoparticle carriers. In melanoma studies, drug-loaded nanoparticles have reduced toxicity and enhanced efficacy by improving drug specificity, pharmacokinetics, and solubility.

Nanoparticles tested for melanoma therapy include liposomes, micelles, dendrimers, polymersomes, carbon-based nanoparticles, inorganic nanoparticles and protein-based nanoparticles. Some, such as inorganic gold nanoparticles, have the added benefit of being used as a diagnostic tool during MRI scans.

While much of the data concerning nanoparticle use for melanoma drug delivery is preclinical, one liposomal formulation, Doxil, is approved for clinical use. Doxil consists of doxorubicin hydrochloride encapsulated in liposomes, and is administered intravenously. However, acquired resistance to Doxil has been an issue in patients with melanoma, and researchers are exploring the efficacy of novel liposomal-based therapies. Gavin Roberts, MD, and colleagues at Penn State College of Medicine have researched a liposomal-based approach to deliver a novel drug, leelamine, to melanoma tumors in mice.

The study, reported in the journal of Molecular Cancer Therapy in October 2014, emphasized that leelamine alone could not be taken orally due to poor intestinal uptake or delivered intravenously as it damages red blood cells. With the use of liposomes, &ldquo;We now have a drug that has the potential to be given to humans that could not be done before,&rdquo; stated Roberts.

The particle/drug combination named Nanolipolee-007 inhibits multiple effector proteins known to promote melanoma tumor growth, including PI3K, MAPK, and STAT3. Roberts is optimistic that targeting multiple melanoma pathways with one therapy could slow the development of resistance.

The discovery of Nanolipolee-007 has been patented by Penn State and licensed to Melanovus Oncology for upcoming US Food and Drug Administration (FDA)-required research before clinical testing.

There may not be an optimal treatment regimen for every patient with melanoma, but novel and complementary approaches to the delivery of therapeutics are resulting in dramatic improvements in toxicity, efficacy, and survival in patients with advanced melanoma.

Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.

Shtivelman E. Immune system-activating drugs in combination treatments may be the next big thing for melanoma. [CancerCommons Website]. Available at: http://www.cancercommons.org/2014/10/20/immune-system-activating-drugs-in-combination-treatments-may-be-next-big-thing-for-melanoma/. Accessed November 15, 2014.

Dianzani C, Zara GP, Maina G, et al. Drug delivery nanoparticles in skin cancers.

Gowda R, Madhunapantula S V, Sharma A, Kuzu OF, Robertson GP. Nanolipolee-007, a novel nanoparticle-based drug containing leelamine for the treatment of melanoma.

Several novel approaches to the delivery of therapeutics for advanced melanoma may improve treatment efficacy and patient survival.

Kate Venmar | Authors

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Programs Prepare for Immuno-Oncology in Clinical Setting

Melanoma Drug Delivery Approaches Advancing