Immunotherapies shift research focus from tumor to technique

Decades of research into the immune system’s role in cancer are paying dividends.

Immune checkpoint blockade has induced significant and durable responses, adoptive cell therapy appears promising, and researchers remain hopeful that combinations of immunotherapeutic approaches may increase the responses observed with cancer vaccines.

Because immunotherapy regulates the immune system instead of targeting specific cancer cells, it has the potential to demonstrate efficacy in all types of solid tumors and hematologic malignancies.

“Immunotherapy is changing the paradigm for cancer treatment because you no longer have to think of the disease as ‘melanoma’ or ‘prostate cancer,’” James P. Allison, PhD, professor and chair of the department of immunology at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “It’s not necessarily about tumor type any longer, but rather about the type of therapy.”

The FDA has approved two immunotherapy agents. The monoclonal antibody ipilimumab (Yervoy, Bristol-Myers Squibb) received approval in 2011 for melanoma, and the vaccine sipuleucel-T (Provenge, Dendreon) was approved in 2010 for advanced prostate cancer.

Many more immunotherapies are in the pipeline for various types of cancer. Yet, biomarkers to identify appropriate patient populations remain elusive, and more research is needed to determine how various immunotherapies can complement each other.

“We’ve had some hints of indications of who will respond to immunotherapy, but they’re not perfect,” Allison said. “There’s nothing yet that rises to the level of argument to decide who should and should not be treated with immunotherapy. However, that issue becomes less important when you see 50% to 80% response rates with combinations. We have to learn how to combine immunotherapies properly.”

HemOnc Today spoke with several immuno-oncologists about the most exciting breakthroughs in the field, the types of immunotherapy that have demonstrated the most promise, and how cancer trials must continually evolve to maximize recent research discoveries.

Releasing the brakes

Of all immunotherapy techniques, efforts to target immune checkpoints with their corresponding monoclonal antibodies have had the greatest impact on patient care. The first breakthrough can be traced to Allison’s development of an antibody to block the CTLA-4 molecule, which downregulates immune T-cell responses to cancer.

“When we saw this, we knew this could be powerful because you’re treating the immune system, not the cancer,” Allison said. “It was a new approach to thinking about cancer therapy. You don’t think so much about the cancer’s biology because it’s not particularly relevant. You don’t need to think about what drug you need to target what driver mutation or what property of the cancer cell, you just regulate the immune system.”

Allison’s discovery — published in Science in 1996 — led to the development of ipilimumab, a CTLA-4 antibody.

F. Stephen Hodi Jr., MD, director of the Melanoma Center and Center for Immuno-oncology at Dana-Farber Cancer Institute and Brigham and Women’s Cancer Center, served as the lead researcher of a phase 3 study, published in TheNew England Journal of Medicine in 2010, that demonstrated ipilimumab extended OS among patients with metastatic melanoma.

“Ipilimumab was the first example of an immune checkpoint blockade that could improve survival,” Hodi said in an interview. “It’s now become a standard for the treatment of melanoma.”

Because immunotherapy can work irrespective of a cancer’s biology, ipilimumab likely will be as effective — if not more effective — in other malignancies as it has been in melanoma, Allison said. In early stage clinical trials, ipilimumab has demonstrated activity among patients with renal, bladder, prostate and pancreatic cancers. It also appeared active in non–small cell lung cancer, although the disease was not thought to be immunogenic.

PD-1 and PD-L1–blocking antibodies such as nivolumab (BMS-936558, Bristol-Myers Squibb) and lambrolizumab (MK-3475, Merck) also have showed promise.

“PD-1 and PD-L1 antibodies are showing an unprecedented level of durable tumor responses,” Antoni Ribas, MD, PhD, director of the tumor immunology program area at UCLA’s Jonsson Comprehensive Cancer Center, told HemOnc Today. “There have been many therapies in metastatic cancers that could lead to an objective response for a period of time, but here we’re engaging the immune system, and when the immune system works well, it leads to durable responses.”

A study by Hamid and colleagues, published in The New England Journal of Medicine in 2013, demonstrated 52% of patients who received the maximum 10-mg/kg dose of lambrolizumab responded. After a median 11 months of follow-up, 81% of patients remained on treatment.

Whereas CTLA-4 releases the brakes on the immune system, the tumor protects itself when the immune system has already been activated through the expression of PD-L1, Ribas said. Therefore, CTLA-4– and PD-L1–blocking antibodies may be combined to increase the number of patients who respond to immunotherapy.

Wolchok and colleagues evaluated concurrent ipilimumab and nivolumab in 53 patients with advanced melanoma. The results, published in The New England Journal of Medicine in 2013, showed 53% of patients who received the maximum dose demonstrated response, defined as tumor shrinkage of at least 80%.

Genentech, MedImmune and other companies have checkpoint blockade antibodies in their pipelines, and preliminary data show these agents confer response rates similar to therapies further along in development, Ribas said.

“These therapies are completely changing the way we treat cancer,” Allison said. “They represent the theory: ‘Treat the patient, not the tumor.’ Some have said, ‘How can you treat the cancer by ignoring it?’ But we’re not ignoring it, we’re directing the immune system against it.”

‘Hunter’ T cells

Researchers also are harnessing the immune system with chimeric antigen receptors (CAR), which bind to T cells and direct them to “hunt” and kill tumor cells.

“The magnitude — including both the frequency and the depth — of the responses we’ve been seeing with CAR T cells have been dramatic and somewhat surprising,” David L. Porter, MD, director of blood and marrow transplantation at the Abramson Cancer Center of the University of Pennsylvania, said in an interview. “We thought we would see some activity, but we didn’t imagine how effective this was going to be. This is a rather remarkable advance considering the majority of patients who we’re treating had few, if any, effective treatment options left.”

At the ASH Annual Meeting and Exposition in December, Porter presented results of a study that evaluated anti-CD19 CAR T-cell therapy in 32 patients with relapsed and refractory chronic lymphocytic leukemia. The overall response rate was 47%. Longer follow-up indicated these responses endured for at least 3 years, with evidence of the T cells detected 5 to 35 months post-infusion.

Grupp and colleagues presented data from 22 children and five adults with acute lymphoblastic leukemia. In that study, 86% of the pediatric population and all five adults experienced a complete remission with the therapy, and evidence of response persisted 20 months. A study by Davila and colleagues published earlier this year in Science Translational Medicine demonstrated an 88% complete response rate among 16 patients with relapsed or refractory B-cell ALL.

Yet, as with other types of immunotherapy, understanding which patients will respond to T-cell therapy — and why response rates have been higher in ALL than in CLL — remains a mystery.

“We have not been able to identify any specific characteristics of the patients, nor of the leukemic cells, that predict whether this immunotherapy will work,” Porter said. “We are making advances in identifying what doesn’t predict response.”

One factor that does not appear to predict response is T-cell dose, according to Porter and colleagues. Their preliminary analysis of a dose-optimization study, also presented at ASH, indicated no correlation between dose and response, nor dose and toxicity. The nature of the approach also may present challenges.

“Particularly for leukemia — because CD19 is a target restricted to B-cell leukemia — there have been tremendous, exciting responses,” Allison said. “However, the CAR therapy and the general use of adoptive T cells are going to be more restrictive in their applicability than the checkpoint blockade antibodies because of the complicated processes that need to be done in order to infuse them into the patients.”

This approach, however, has enabled the personalization of immunotherapy.

“A drug is manufactured essentially from the patient’s own T cells; therefore, it’s highly individualized,” Porter said. “But the same vector is used for every patient because CD19 is the same in every patient. This therapy potentially offers the best of a one-size-fits-all therapy and personalized medicine.”

T cells in solid tumors

The next challenge in adoptive T-cell therapy is translating its success in blood cancers to solid tumors.

Unlike in hematologic malignancies, for which T cells are made to target CD19 on B cells, targets in solid tumors are less clear, and early studies have been primarily unsuccessful due to off-target toxicity.

“CD19 is not tumor-specific; it’s on normal B cells, without which patients can live and be managed successfully,” Porter said. “That is not the case with a target that is, for example, co-expressed in normal lung, bowel or pancreatic tissues. We need a target that is tumor-specific, and right now there are very few molecules that one can target in such a tumor-specific manner.”

However, steps have been made to identify targets and address toxicity.

Another Penn study by Beatty and colleagues, published in 2013 in Cancer Immunology Research, evaluated adoptive T-cell therapy in two patients with solid tumors. One patient had advanced mesothelioma and the other had metastatic pancreatic cancer.

Researchers engineered the CAR T cells using microRNA to target mesothelin in tumors. The patient with mesothelioma received three CARTmeso cell infusions and demonstrated stable disease. After eight infusions, the patient with pancreatic cancer demonstrated a 40% reduction in mesothelin-carrying tumor cells.

In March, Bellicum Pharmaceuticals announced the launch of a partnership with NCI investigators to conduct a phase 1 dose-escalation trial of third-generation, GD2-targeted CAR T cells in solid tumors.

The T cells are manufactured to contain a safety switch that enables their inactivation in the instance of off-target toxicity. Researchers plan to enroll 36 pediatric patients with sarcoma or other non-neuroblastoma tumors that express GD2.

“I’m extremely excited about the potential for T-cell therapy in solid tumors, although there are great challenges trying to identify the best targets,” Porter said. “Looking at the pace that this field has been moving, and seeing what has been made possible, I am extremely optimistic that this has the potential to change the paradigm in cancer therapy by using cell-directed immunotherapy to develop ‘hunter’ cells that can specifically recognize solid tumors.”

Vaccine development

The same approach behind adoptive cell therapy and immune checkpoint blockade applies to cancer vaccines, as the immune system is activated to build up a response against cancer cells.

“The FDA approval of Provenge for prostate cancer provides proof of principle for vaccines in cancer therapy and sets the stage for the rest of us who are interested in developing vaccines to move forward,” said Leisha Ann Emens, MD, a member of the tumor immunology research program at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

Other promising vaccines are melanoma-associated antigen-A3 (MAGE-A3, GlaxoSmithKline) and talimogene laherparepvec (Amgen), referred to as T-VEC.

A retrospective analysis presented at the 67th Society of Surgical Oncology Annual Cancer Symposium in March included 295 patients with advanced melanoma. Results indicated 64% of patients experienced tumor shrinkage with T-VEC. Responses were observed in tumors that were injected with the vaccine, as well as those that were not, according to a press release from Amgen.

However, cancer vaccines have not generated as much excitement as other forms of immunotherapy due to their unique challenges.

“We’ve always used vaccines almost exclusively for prevention when there’s no disease around,” Emens said. “The trouble with cancer vaccines is, we’re applying them to a situation where a disease is present and well established, and the immune system has already learned to tolerate it or ignore it. Those are a lot of high hurdles for a vaccine to overcome.”

Recent setbacks have compounded the issue. In September, GlaxoSmithKline reported MAGE-A3 failed to meet its primary endpoint of DFS among patients with melanoma. In March, the company announced the vaccine failed to meet the same endpoint among patients with NSCLC. However, researchers continue to try to identify a subset of patients who may benefit from the vaccine.

Again, combinations may be key to improving efficacy.

“As a single modality, we don’t know if vaccines will pass the critical litmus test on their own,” Hodi said. “The next round of excitement for immunotherapy is likely to concern combinations of checkpoint blockades and vaccines.”

Emens has developed a cell-based vaccine for breast cancer that expresses HER-2. When preceded by low doses of cyclophosphamide, the vaccine has demonstrated enhanced immune activity. Clinical trials are underway to evaluate the vaccine in combination with trastuzumab (Herceptin, Genentech) for patients with HER-2–positive breast cancer.

“Combining a vaccine with the standard drugs like cyclophosphamide or Herceptin, or checkpoint blockade agents, is going to increase the likelihood that a vaccine will have an impact,” Emens said. “For cancer in the later-stage disease setting, this is surely going to be the way to go.”

Other investigations are underway to evaluate T-VEC with ipilimumab and lambrolizumab.

A phase 3 study by Butts and colleagues, published in January in The Lancet Oncology, evaluated the vaccine tecemotide (Stimuvax, Merck KGaA) in patients with NSCLC. Although the data indicated the vaccine did not extend OS on its own, a subset of patients who received concurrent chemotherapy and radiation before the vaccine demonstrated benefit.

The nature of vaccines also may require earlier treatment.

“You can increase the likelihood of a vaccine having an impact by moving it earlier in therapy,” Emens said. “Particularly among patients with metastatic disease who have been treated to the point where their burden of disease is very low, or among patients who are at high risk to recur, vaccines can be used to prevent relapse. Really, the key moving forward is understanding how best to use vaccines.”

Seeking a cure

The rapid evolution of immunotherapy research and the growing number of immunotherapy agents in development have prompted researchers to question the best way to assess these therapies in clinical trials.

“It’s an exciting time. We finally have a handle on immunotherapy and can now think about caring for patients,” Allison said. “We’re moving as fast as we can to benefit the most patients with as many types of cancer possible.”

Although the trial and registration for ipilimumab took nearly 5 years, researchers knew the agent was efficacious 2 years before the trial ended, he said.

“With research moving so quickly, and so many new drugs in development, we can’t take 5 years to register every single drug, and another 5 years to do it again with the combinations, and then have to do that again with every type of cancer,” Allison said.

The traditional structure of clinical trials — progressing from preliminary safety evaluation in phase 1 to an efficacy comparison with the standard of care in phase 3 — must be rethought, he said.

OS as the benchmark for drug effectiveness also may impede the process.

“Hundreds of millions of dollars have been spent developing drugs that will only shift the median survival by a few months,” Allison said. “That’s been enough to receive FDA approval, which is OK because patients benefit, especially if they experience improved quality of life. However, more emphasis now needs to be placed on durable response.”

Emphasis should shift away from median survival on the Kaplan-Meier curve and instead focus on increasing the tail of the curve, he said.

“If you can get responses to last a decade or more, it’s possible the ‘cure’ word can start to be used,” Allison said. “People stay away from that word, but it’s what we should be seeking.”

In addition, immunotherapy trials should not be a last resort for patients.

“Clinicians need to understand that it’s better to refer patients for immunotherapy research earlier than they’re used to thinking about for trials,” Emens said. “There’s a window of opportunity in patients to use a novel therapy before their immune system has been beaten down by standard therapy, and before their disease is so advanced.”

Despite these challenges, it is clear immunotherapy holds significant promise.

“All of the advances that have been made are based on knowledge about patients. They’re not random things,” Ribas said. “This means significant advances will continue, as each new breakthrough leads to further understanding of how best to combine these therapies and make them broadly applicable. I anticipate that in the near future, we’ll be testing for durable responses with immunotherapy in the majority of cancer patients. There will be a significant number of patients in whom this will work, and it will be the standard of care.” – by Alexandra Todak

References:

Beatty GL. Cancer Immunol Res. 2014;2:112-120.

Butts C. Lancet Oncol. 2014;15:59-68.

Davila ML. Sci Transl Med. 2014;6:224ra25.

Hamid O. N Engl J Med. 2013;369:134-144.

Hodi FS. N Engl J Med. 2010;363:711-723.

Emens LA. Expert Rev Anticancer Ther. 2012;12:1597-1611.

Leach DR. Science. 1996;271:1734-1736.

Wolchok JD. N Engl J Med. 2013;369:122-133.

The following were presented at the ASH Annual Meeting and Exposition; Dec. 6-10, 2013; New Orleans:

Grupp SA. Abstract #67.

Porter DL. Abstract #873.

Porter DL. Abstract #4162.

For more information:

James P. Allison, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0901, Houston, TX 77030; email: jallison@mdanderson.org.

Leisha Ann Emens, MD, can be reached at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St., Room 409, Bunting Blaustein Cancer Research Building, Baltimore, MD 21231; email: emensle@jhmi.edu.

F. Stephen Hodi Jr., MD, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: stephen_hodi@dfci.harvard.edu.

David L. Porter, MD, can be reached at The University of Pennsylvania, Hematology-Oncology, 3400 Civic Center Blvd., PCAM 2 West Pavilion, Philadelphia, PA 19104; email: david.porter@uphs.upenn.edu.

Antoni Ribas, MD, PhD, can be reached at UCLA’s Jonsson Comprehensive Cancer Center, 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781; email: aribas@mednet.ucla.edu.

Disclosure: Allison reports a paid consultant role with Bristol-Myers Squibb. Emens reports research funding from and advisory roles with Bristol-Myers Squibb, Genentech and Roche. Hodi reports research funding from and a consultant role with Bristol-Myers Squibb. Porter reports honoraria from Bristol-Myers Squibb, Celgene and Roche, and royalties on patents licensed to Novartis. His spouse is employed with Genentech. Ribas reports consultant roles with Amgen, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Millennium Pharmaceuticals, Novartis and Pfizer, as well as research funding from Pfizer.Disclosure: Sullivan reports no relevant financial disclosures.

 

Should immunotherapy be used as front-line therapy for all cancers?

Immunotherapy should be considered for front-line therapy among patients with advanced cancer.

Published data from early clinical trials of agents blocking inhibitors of lymphocyte function such as CTLA-4 or the PD-1/PD-L1 pathway indicate substantial activity in metastatic melanoma, and also clinically meaningful activity in subsets of patients with other malignancies, including non–small cell lung cancer and renal carcinoma (Wolchok JD. N Engl J Med. 2013;369:122-133. Topalian SL. N Engl J Med. 2012;366:2443-2454. Hamid O. N Engl J Med. 2013;369:134-144). Exploration of these agents in other malignancies is ongoing, but objective responses have already been reported in multiple other tumor types. The most impressive feature of the clinical activity of immune therapy — including cytokines such as interleukin-2, the immune checkpoint inhibitors and adoptive lymphocyte transfer — has been the ability to produce long-term unmaintained responses (possibly cures) in some patients with advanced metastatic disease, including patients whose disease progressed on multiple other therapies.

As oncologists, we remain agnostic as to the type of therapy that can provide our patients with the greatest benefit. Most patients seek treatments that are given over a limited period of time and will eliminate all disease, so that they can return to a normal life without any persistent adverse effects — or continued treatment — that would diminish quality of life. For most molecularly targeted agents and chemotherapy in most indications — including those that prolong survival and produce substantial clinical benefit — achievement of long-term unmaintained responses has been an elusive goal.

Thus, in advanced cancers in which immunotherapy has been shown to produce long-term complete remissions even in a small subset, strong consideration should be given to administration of the immunotherapy as the front-line treatment. In disease unresponsive to or progressing after immunotherapy, palliative targeted therapies or chemotherapy can be offered in second-line or subsequent lines of treatment. Although unknown, the clinical benefit of a targeted therapy or chemotherapy is unlikely to be substantially diminished by a delay in administration of 12 to 20 weeks (to allow for assessment of immune therapy responsiveness), and possibly could be enhanced by prior immune therapy. The effect of immunotherapy on safety of subsequent non-immunotherapies — or the possibility of adverse interactions through close sequencing — remains unknown.

In clinical medicine, there are few absolute rules, and there are always many unanswered questions. For example, the positive or negative impact of prior therapy on the efficacy of immunotherapy is unknown; theoretically, a targeted therapy given first may improve the outcome of a subsequent immune therapy by modifying tumor–host immune interactions. Certain patients present with both large tumor burdens and rapidly progressive disease. Despite the presumed improved effectiveness and rapid onset of action of new immunotherapy regimens — for example, the combination of ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (BMS-936558, Bristol-Myers Squibb) in metastatic melanoma — it may still be prudent in select patients to begin with targeted molecular therapies.

Despite the current impressive successes of immunotherapy, the field is in its infancy. There are multiple other immunologic targets (antagonists of immune inhibitory pathways, co-stimulatory agents, manipulation of tumor microenvironment lymphocyte infiltration) as yet unexplored, which will likely increase efficacy and broaden the scope of use. Advances in predictive biomarkers will aid both in selection of agents for an individual and in identifying those patients in which front-line immune therapy will have greatest impact, rendering the sequence question moot.

Mario Sznol, MD, is a professor of internal medicine at Yale Cancer Center. He can be reached at Yale Cancer Center, P.O. Box 208028, 333 Cedar St., New Haven, CT 06520-8028; email: mario.sznol@yale.edu. Disclosure: Sznol reports paid consultant and scientific advisory board roles with Amgen, Amphivena, Anaeropharma, BeiGene, Bristol-Myers Squibb, Genentech/Roche, Immune Design, Kyowa-Kirin, Lion Biotechnologies, MedImmune, Merus, Nektar, NeoStem and Seattle Genetics.

Targeted therapies may be the preferred front-line therapy over immunotherapy.

With options come choices. Over the past 4 years, the treatment landscape has radically shifted for metastatic melanoma patients generally and, most specifically, for those patients whose tumors harbor a BRAF mutation. The major clinical question for medical oncologists treating patients with melanoma is how to sequence immunotherapy and BRAF-targeted therapy. Unfortunately, there is no prospective data to help guide this discussion, so we must rely on retrospective analyses and anecdotal experiences to make the best recommendations we can for our patients.

As a general principle, if a treatment option exists that comprises a short duration of therapy leading to durable remissions, this should be considered in the front-line setting. It is clear that immunotherapies such as high-dose IL-2, ipilimumab, and the anti-PD-1 antibodies nivolumab and MK-3475 (Merck) are associated with durable responses in a minority of patients with melanoma. Choosing immunotherapy over BRAF-targeted therapy is thus a reasonable choice, given that the percentage of patients with durable responses to these therapies likely ranges from 10% to 30%. With that said, standard BRAF-targeted therapy approaches, either with single-agent BRAF inhibitors (eg, dabrafenib [Tafinlar, GlaxoSmithKline] and vemurafenib [Zelboraf, Hoffmann-La Roche]) or with the combination of BRAF and MEK inhibitors (such as the FDA-approved combination of dabrafenib and the MEK inhibitor trametinib [Mekinist, GlaxoSmithKline]) result in temporary control of disease in nearly all patients, and they are associated with durable benefit in a minority of patients. For this reason, it is worth considering upfront BRAF-targeted therapy over immunotherapy in any BRAF-mutant patient, though in our practice we reserve upfront BRAF inhibitor therapy for a subgroup of patients. A persistent challenge for researchers in the field is to elucidate the factors that predict long-term benefit for any given patient.

Any BRAF-mutant melanoma patient with a contraindication for immunotherapy (eg, moderate to severe autoimmune disease) is an obvious candidate to receive upfront BRAF-targeted therapy. Additionally, patients with rapidly progressing, symptomatic metastatic disease often do not have time to wait the weeks to months for an immunotherapy response and must receive front-line BRAF-targeted therapy with the high likelihood of short-term benefit from this type of treatment. Whether these patients may be successfully transitioned to immunotherapy following a brief course of BRAF-targeted therapy has not been well studied to date, but anecdotally has not been met with much success. Frustratingly, many patients do not fit into either of these categories, and physicians lack an evidence-based method for selecting one modality over another.

Ryan J. Sullivan, MD, is an instructor in the department of medicine at Harvard Medical School and an assistant in medicine at the MGH Cancer Center of Massachusetts General Hospital. He can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA, 02114; email: rsullivan7@partners.org. Disclosure: Sullivan reports no relevant financial disclosures.