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specific neoantigens have enormous potentials for the development of personalized cancer immunotherapies both as a vaccine as well as cell-based neoantigen therapies.
Several studies demonstrated graft-vs-tumor responses in transplantable murine
hematopoietic tumors using adoptive transfer of bone marrow cells or lymphoid cells
[78, 81, 82]. In other words, immune responses generated by grafts induced antileukemic
effects. Studies reported that adoptive transfer of allogenic bone marrow but not of
syngeneic bone marrow resulted in tumor clearance in rodents [78, 81, 82]. Dominant
graft-vs-host disease (GVHD) constrained studies aimed at evaluating graft-vs-tumor
responses in humans. However, some studies did emphasize that adoptive transfer of
patient’s own or donors’ leukocytes could be a suitable strategy to generate antitumor
responses in humans. Southam et al. reported that nearly half of the patients who were
cotransplanted with patient-derived leukocytes from peripheral blood and autologous
tumor cells demonstrated tumor regression [81, 83]. They also noted antitumor effect
when leukocytes from donors were transplanted although the results were inconsistent.
Later, Weiden et al. demonstrated the clinical effectiveness of the adoptive transfer
approach using allogenic hematopoietic stem cell transplant for leukemia [82]. In their
study, leukemia patients received bone-marrow transplants from syngeneic (monozygous
twins) or allogenic (HLA-A, HLA-B, and HLA-D identical siblings) donors. They noted
that the probability of remaining leukemia-free was highest among allogenic bone marrow recipients who developed moderate to severe acute or chronic GVHD (Grade II–IV
GVHD). The probability of remaining leukemia-free was only slightly but not significantly improved in allogeneic recipients who developed Grade 0–I GVHD and in syngeneic bone marrow recipients. Notably, both these studies suggested that lymphocytes
could be key players in mediating antitumor responses thus underlining the viability of
such an approach for therapeutic application. A better understanding of the role of T cells
in the graft-vs-tumor effect and subsequent direct demonstration that T cells are a prime
players in mediating antitumor immunity provided a rationale for the development of
T-cell-based ACTs. Currently, T cell-based ACTs could be broadly categorized into
(a) naturally occurring tumor-infiltrating lymphocytes (TIL), (b) TCR engineered lymphocytes (TCR-T), and (c) chimeric antigen receptor CAR-T). In this chapter, we focus
on ACTs using TILs since TCR-T and CAR-T have been extensively covered in other
chapters.
411Personalized cancer immunotherapy
9. Tumor-infiltrating lymphocytes: A rich source of tumor specific
T cells
A major boost in manipulating T cells for ACTs for cancer treatment came after the
discovery of T cell growth factor interleukin-2 (IL-2). Notably, T cells could be grown
ex vivo for several days in presence of T cell growth factor interleukin-2 (IL-2), often
without loss of effector functions [78, 84]. T lymphocytes infiltrate tumors but can
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undergo a state of unresponsiveness or hypo-responsiveness and fail to mount antitumor
responses. It was demonstrated in several studies, in particular by Rosenberg and colleagues, that incubation of human peripheral blood lymphocytes or murine splenocytes
in presence of IL-2 gave rise to cells capable of lysing fresh syngeneic or autologous
tumors [85–88]. These studies found that the lytic cells termed as lymphokine-activated
killer (LAK) cells exhibited broad specificity for a variety of fresh tumors but did not lyse
fresh normal cells. Additionally, LAK cells expanded in vivo under the influence of IL-2
and retained antitumor lytic activity [89]. Administration of high dose IL-2 alone, intravenous injection of immune lymphocytes expanded in IL-2 or concomitant administration of IL-2 together with cell transfers enhanced the antitumor function of lymphocytes
in experimental animal models [78, 90–97]. Allogenic cell transfers result in a dominant
GVHD limiting the beneficial antitumor responses. On the other hand, it was conceived
that patient’s own (autologous) T cells could be cultured ex vivo in presence of IL-2,
activated, expanded, and then reinfused to overcome; (a) unresponsiveness of T cells
and (b) GVHD responses associated with allogenic cell transfers.
Based on the success in animal models, human studies were conducted which demonstrated that systemic administration of LAK plus IL-2 results in complete and durable
tumor regression in some patients with metastatic melanoma [98]. This encouraging data
resulted in further refinements of T cell-based ACTs that were pioneered by Rosenberg
and colleagues at the National Cancer Institute in the late 1980s. Initially, lymphocytes
for ACTs were obtained by repeated lymphocytaphereses [98] from peripheral blood. In
later studies, Rosenberg and colleagues found that syngeneic TILs, expanded in IL-2,
mediated tumor regression of established lung and liver tumors in mice [99]. Adoptive
transfer of IL-2 expanded TILs was 50–100 times more effective than IL-2 expanded
LAKs. Human TILs were obtained from resected melanomas and cultured in presence
of recombinant IL-2. These in vitro expanded TILs were highly cytotoxic against autologous melanoma tumor cells but not against fresh normal cells [100]. Notably, they found
that tumor-associated specific killer cells could be expanded about 95 652-fold with
retention of their tumor lysis function [100]. These studies resulted in the development
of ACT with autologous TILs using an approach as summarized in Fig. 3. In their initial
trial Rosenberg and colleagues observed an objective response rate of 34%. And although
several patients showed complete response, the median response rate was only 4 months
[102, 103]. Later studies found substantial increases in the persistence of transferred cells as
well as incidence and duration of clinical response (Fig. 3) [78] when a lymphodepletion
preparative regimen consisting of 60 mg/kg cyclophosphamide for 2 days and 25 mg/m
2
fludarabine administered for 5 days was added prior to ACT [104]. In total 93 patients
with metastatic melanoma, 20 (22%) patients had complete tumor regression with 19 of
whom were in complete remission 3 years after treatment [78, 81, 104].
Improved success of TIL-based ACTs in melanoma with the inclusion of
lymphodepletion preparative chemotherapy before cell transfers has ignited interest in
Fig. 3 General scheme of culturing naturally occurring TILs for use in ACTs: Preparation of pure cultures of tumor-infiltrating lymphocytes for use in clinics have been described in detail [78, 101]. Tumor
are resected from patients usually under anesthesia and dissected into small fragments (usually
3
5mm
) [78, 101] or single-cell suspensions are prepared by enzymatic digestion [78]. Tumor fractions
are grown individually in high dose IL-2 (6000 IU/mL). Under the influence of IL-2, lymphocytes overgrow and destroy tumors within 2–3 weeks [78]. Using this approach pure culture pf lymphocytes can
be grown and tested for their cytotoxicity by co-culturing IL-2 primed lymphocytes and tumor cells.
Individual cultures that show high toxicity against target tumors can then be rapidly grown in the presence of excess irradiated feeder lymphocytes, an antibody targeting the epsilon subunit within the
human CD3, and IL-2. With this strategy, Rosenberg and Restifo could obtain 10
approximately 5–6 weeks for infusion in patients. Later clinical trials used a lymphodepletion prior
to T cell transfer. The most followed lymphodepletion preparative regimen consisted of 60 mg/kg
cyclophosphamide for 2 days and 25 mg/m fludarabine administered for 5 days. Following
lymphodepletion patients were infused with cells and IL-2 at 720 000 IU/kg to tolerance [78].
11
lymphocytes in
413Personalized cancer immunotherapy
understanding cellular and molecular mechanisms through which lymphodepletion
regimens enhanced functions of infused T cells [78, 105–107]. In mouse models as well,
lymphodepletion prior to cell transfer showed manifold improvement in the effectiveness
of ACTs [78]. In human trials and clinics, lymphodepletion enhanced the persistence of
transferred cells. In their earlier trials when lymphodepletion was not performed, transferred T cells could be barely detected in patients, however, later trials, incorporating the
lymphodepletion regimen, documented enriched CD8 T cells in patient’s peripheral
blood [78, 106, 108]. Lymphodepletion results in the induction of cytokines and growth
factors, such as IL-7 and IL-15, that are involved in the homeostasis of T cells [107, 109].
Induction of these cytokines has been proposed to promote the expansion of transferred
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T cells in the absence of endogenous lymphocytes [78]. Mouse studies provide further
mechanistic insights. In mouse tumors, there are increased frequencies and numbers
of suppressive cells such as myeloid-derived suppressor cells (MDSCs) and FoxP3
+
regulatory T cells (Tregs) that could dampen immunogenicity of native or transferred T cells
[78, 110]. Although preparative chemotherapies in humans deplete several of these sup-
pressive myeloid and lymphoid cells from circulation, the reappearance of FoxP3 inhibitory T cells after lymphodepletion is inversely correlated with the clinical response of
ACTs [111]. Lymphodepletion regimens could also mobilize commensal microbiota
across the mucosal barriers and microbe-derived toll-like receptor ligands could act as
adjuvants to enhance the effects of ACTs [78, 109]. The intensity of lymphodepletion
is an important variable not only in the persistence and expansion of TIL-based ACTs
but also in CAR-T cells [79, 112]. From these basic and preclinical studies, it appears
that immune ablation would constitute an essential component of future ACTs to treat
cancers. As more and more mechanistic insights are gained, a targeted approach could be
employed to specifically ablate specific cell types and/or administer cells or molecules that
support expansion, persistence, and antitumor functions of transferred T cells.
In melanomas, TIL-based ATCs could be successful because lymphocytes cultures
with tumor-specific recognition and cytotoxicity could be consistently harvested. Studies
have now documented that melanoma TILs consist of a pool of lymphocytes that recognize tumor-associated or tumor-specific antigens [78, 113–115]. In fact, the responsiveness of melanoma to a variety of immunotherapeutic approaches such as the
ACT, checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 might be attributed
to high-frequency of mutations present in melanomas that are targeted by T cells [78,
113–115]. The success of TIL-based ACTs depends upon the presence of tumor-specific
T cells in the tumors. Although TILs can be grown from a variety of tumors, unlike melanomas tumor-specific TILs cannot be consistently harvested. This has limited the use of
TIL-based ACTs in other types of cancers, mainly solid tumors where other forms of
immunotherapies such as checkpoint inhibitors have also shown limited or no success
at all. As we discuss in the following section, massive attempts are being made to identify
antigens that are recognized by TILs to extend the success of ACTs in melanomas to
other commonly occurring cancers. And the future is poised for significant discoveries
that could potentially change the landscape of cancer treatment or at least aid the current
regimens for a more effective cure of cancers.
10. Tumor neoantigens and their role in tumor immunity
Effects of blockade of PD-1/PD-L1 are not restricted to melanoma but have been
reported in other types of cancers such as nonsmall-cell lung cancer (NSCLC), bladder
cancer, and microsatellite-instable cancers [9, 15, 24, 25, 30, 78, 116–118]. Although the
PD-1/PD-L1 axis could likely influence several immune cells, there is compelling
evidence that has established beyond doubt that T cell reactivity against the tumors is the
major driver of tumor regression [18, 24, 25, 119, 120]. The positive outcome of antiPD-1 therapy in melanoma is correlated with CD8 T cell infiltrates [18, 24, 25]. Furthermore, studies in mice and cancer patients have supported a notion that adoptive transfer
of minimally differentiated CD8 T cells show better antitumor activity compared to terminally differentiated counterparts [121]. In cancer immunotherapy, much of the work
has focused on CD8-T cells [24, 25, 78]. However, CD4 T cells can also mediate tumor
rejection [24, 25, 78]. For instance, a study found that TIL cultures from a patient with
cholangiocarcinoma consisted of CD4 T cells that recognized ERBB2IP mutation,
restricted by the MHC class 2 antigen HLA-DQ O6. Notably, while bulk TILs failed
to show any objective clinical response, when TILs were enriched to contain more than
95% ERBB2IP mutation reactive TILs and reinfused into the patient, a dramatic regression of liver and lung metastasis was noted [78, 122]. The antitumor role of CD4 T cells
extends beyond the mere support of the antitumor functions of CD8 T cell [78]. Overall,
the state of polarization of CD4 T cells seems to play determining role in their antitumor
functions [78, 123]. Adoptive transfer of T helper 17 cells can promote long-lived
antitumor immunity [123]. Cumulatively, evidence from TIL-based ACTs and checkpoint inhibitors imply that, in the substantial number of patients, CD4 and CD8 T cells
recognize tumor antigens presented in the context of major histocompatibility class
(MHC) 2 and 1, respectively. Understanding the nature of antigens recognized by
T cells in the tumor microenvironment has substantial relevance for personalized cancer
immunotherapies.
The first-class of tumor antigens consists of cancer rejection epitopes that are generated by nonmutated tumor differentiation proteins that arise due to activation of oncogenic pathways and epigenetic changes in genes encoding them. This cancer-germline
(C/G) antigens are highly expressed in the tumor while their expression in healthy tissues
is low or restricted to immune-privileged sites [24, 25, 124]. Melanocyte differentiation
proteins, MART-1 and gp100 are recognized by melanoma TILs [78, 113, 114]. This
raised marked excitement in the field of cancer immunotherapy because if such C/G
antigens could be discovered in tumors, they could be utilized in large patient populations
[25, 125]. Melanoma patients who showed tumor regression with TILs therapy did not
develop major life-threatening toxicities [78]. On the other hand, when T cell receptors
(TCRs) with high affinity for MART-1 and gp100 were inserted into lymphocytes for
the ACT, substantial target toxicity against healthy melanocytes were observed without
any antitumor activity [126]. Such observations had implications for future studies on the
discovery of C/G antigens, since on target, off-tumor toxicities could limit their potential
clinical use. It should be mentioned here that T cells directed against NY-eso-1, a C/G
antigen, have shown an antitumor effect [24, 127, 128]. Besides, more intensive studies
are required to ascertain the potential contribution of C/G antigen reactive T cells in
antitumor immunity and/or on target, off-tumor toxicities [24].
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The second class of tumor antigens is formed by DNA alterations such as single nucleotide changes; insertion deletions that accumulate in the tumors and lead to frameshift
and structural variants. Depending upon their characteristics, products of these mutated
genes can be processed and presented to T cells by MHC molecules [24, 25]. These
so-called neoantigens are strictly expressed by tumors and not expressed by healthy
tissues, and from an immunological perspective, constitute “nonself” to the host [24,
25]. There are two major implications; (1) stochastically if neoantigen-specific T cells
arise after positive selection in the thymus, central tolerance mechanisms that delete
self-reactive T cells would not eliminate them and (2) neoantigen-specific T cells would
be highly specific against tumors and not be associated with on target, off-tumor toxicities
in normal tissues [24, 25]. Interestingly, discoveries that mutant peptides or neoantigens
in human melanomas were targeted by autologous cytotoxic T cells were being made
concurrently with the discovery of C/G antigens [25, 129, 130]. A study by Lennerz
et al. documented that the response of autologous T cells to a human melanoma is dominated by mutated antigens [131]. The authors further concluded that cellular antitumor
responses were highly variable among individuals and effective cancer immunotherapy
required highly individualized or personalized monitoring of primary targets of the autologous T cell responses [131]. However, unlike C/G variants, the discovery of
neoantigens lagged as dissecting T cell reactivity on patient specific basis was a technically
demanding and cumbersome exercise until recently [25, 129–131]. The dawn of the next
generation sequencing (NGS) era combined with parallel developments in the field of
T cell epitope discoveries, rejuvenated interest in the discovery of neoantigens [24,
25]. Studies in mice and, subsequently, in humans used the NGS exome sequencing
approach and demonstrated that cancer genome data could be utilized for the discovery
of neoantigens and assay of T cell reactivity against these neoantigens [24, 25, 132–134].
In Fig. 4, we provide a schematic of a generalized approach to neoantigen discovery.
Using this or similar approaches, neoantigens and T cell reactivity to these neoantigens
have been reported in several different forms of cancers such as NSCLC, ovarian cancer,
squamous cell carcinoma of the head and neck, cholangiocarcinoma, and colorectal cancer [26, 122, 135– 137]. These studies cataloged enhanced generation, detection, or reactivity of neoantigen-specific T cells, which is indicative of their essential antitumor role
[24, 25]. As discussed, earlier consistent reports of the correlation between tumor muta-
tional burden (TMB) and clinical responses to cancer immunotherapies further establish
the critical role played by neoantigen-specific T cells in antitumor immunity [24, 25, 30,
78, 118, 138–140]. We have emphasized earlier that biomarker discovery constitutes an
essential part of personalized cancer immunotherapy and TMB is now an approved biomarker for cancer immunotherapy. Combining TMB with parameters that define T cell
fitness, function, etc., may further enhance their clinical value as biomarkers in the future.
[24, 25, 60, 141]. Besides, there is general agreement among researchers that neoantigen
discovery would extend the benefits of cancer immunotherapy to cancer types where
current regimens have failed or shown poor results [24, 25].
417Personalized cancer immunotherapy
Fig. 4 General scheme of neoantigen discovery pipeline: Healthy cells and tumor cell exome
sequences are obtained using next-generation high throughput exome sequencing platform to identify tumor-associated mutations. Expression of tumor variants is ascertained using RNA sequencing. In
silico methods are used to identify putative neoantigens. Appropriate in silico filtering methods such
as prediction of peptide binding to patient’s MHC haplotypes, peptide cleavage products generated by
proteosome, etc., are applied to narrow down on identified tumor variants for experimental validation.
In addition to in-silico methods, neoantigen identification can be greatly aided by using mass spectrometry analysis of MHC-associated peptides. Peptides predicted/identified by in-silico and/or mass
spectrometry approaches can then be synthesized and used to assay for neoantigen-specific T cells
through MHC multimer-based screen or cytokine induction by peptide stimulation.
11. Neoantigen reactive T cells; broadening the landscape of
personalized cancer immunotherapies
The most successful cancer immunotherapies to date, checkpoint inhibitors, are
not specific against tumors and can have profound autoimmune toxicity. Correlation
between TMB or TILs with the success of cancer immunotherapies implies that
approaches that will increase the number of neoantigen-specific T cells and their antitumor functionality are expected to broaden the benefit of cancer immunotherapy to
(1) large patient groups and (2) diverse tumor types. Neoantigen-specific T cells can
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be increased using (1) vaccination strategy to expand neoantigen T cells in vivo or (2)
adoptive cell therapies where neoantigen-specific T cells could be expanded/enriched
ex vivo and infused into patients.
12. Neoantigen vaccines
Several studies have demonstrated that vaccination strategy would be an effective
way to broaden neoantigen-specific T cells responses [25]. Castle et al. tested the immunogenicity and specificity of 50 validated mutations identified using next-generation
exome sequencing [133]. They found that one-third of the peptides were immunogenic,
with 60% in this group eliciting immune responses directed against the mutated sequence
as compared with the wild-type group [133]. In tumor transplant models they found that
peptide immunization conferred in vivo tumor control. Thus, mutated epitopes with single amino acid changes could be used to develop effective vaccines [133]. They used long
peptides covering the 50 mutations which could elicit both CD8 T and CD4 T cell
responses but found a preponderance of CD4 T cell responses [133]. Gubin et al. immunized mice with synthetic long peptides that contained MHC class I epitopes discovered
using neoantigen discovery pipeline [142]. Immunization-induced tumor regression was
comparable to that observed after T cell checkpoint blockade [142]. Other studies in
mice that used defined neoantigens also demonstrated enhanced tumor control following
vaccination [143, 144]. In human studies, vaccination with neoantigens enhanced the
magnitude of T cell responses and/or boosted T cell function. Kenter et al. investigated
immunogenicity and efficacy of a synthetic long-peptide vaccine in women with human
papillomavirus (HPV)-16-positive, high-grade vulvar intraepithelial neoplasia [145].
They reported that all patients had vaccine-induced T cell responses [145]. Moreover,
patients with complete response after 3 months had a higher interferon-gamma (IFN-γ)
producing CD4 T cells and stronger proliferative responses compared with the group that
did not respond [145]. In addition, all patients with a complete response had HPV-16 specific CD8 T cell responses [145]. Carreno et al. found that immunization of three-stage III
melanoma patients with in-silico predicted HLA-A*02:01 restricted neoepitopes, loaded
onto autologous dendritic cells, generated CD8 T cell responses. Aside from boosting preexisting CD8 T cells, vaccination resulted in the appearance of previously undetected
Tcells[146]. More clinical trials that tested the efficacy of the neoantigens vaccine as adju-
vant therapy following surgery reported objective clinical responses in melanoma patients
[147, 148]. Importantly patients who did not respond to neoantigens immunotherapy
showed responsiveness following anti-PD-1 therapy [147, 148]. Thus, neoantigen vaccines
could be used in combination with checkpoint blockade therapies. Such combinatorial
approaches could minimize toxicity associated with high dosage checkpoint inhibitor
blockade therapies [25].
As discussed earlier, both CD4 and CD8 T cells can effectively induce tumor regression. But, from a perspective of vaccine development, there is less clarity on whether
CD8 T cells or CD4 T cells should be targeted [25]. In addition, studies indicate induction of novel T cells and not an expansion of preexisting T cells should be the focus of
cancer vaccine development [25]. Other approaches, such as the discovery or optimization of adjuvants that boost the functionality of neoantigen-specific T cells for effective
antitumor functions, are required [25]. The field of cancer neoantigen vaccine would also
benefit from the discovery of effective delivery technologies that are being intensively
pursued [149].
13. Neoantigen-specific T cells for adoptive cellular
therapies
Neoantigen-specific T cells may be expanded ex vivo using approaches similar to
those discussed above (Fig. 3). Alternatively, TCR sequences with known specificity
could be introduced into peripheral blood T cells. Rosenberg and colleagues have utilized an approach to enrich neoantigen-specific T cells from TIL cultures [122, 136, 150].
Transfer of enriched neoantigen-specific CD4 T and CD8 T cells have shown clinical
success in inducing tumor control in patients with metastatic cholangiocarcinoma
[122], colorectal cancer [136], and breast cancer [150]. In other studies, enrichment of
neoantigen-specific T cells had limited clinical success [151]. As discussed before, the dis-
covery of neoantigens and neoantigen-specific T cells is just the first step. The tumor
microenvironment can induce a long-lasting state of hyporesponsiveness in tumorinfiltrating T cells, which may not eliminate tumors effectively [24, 25, 78] . In addition,
current technologies employed to obtain enough numbers of T cells for infusing into
patients are rigorous and it is often difficult to obtain a sufficient number of cells [24,
25, 78]. To overcome issues associated with obtaining enough functional T cells other
approaches are being explored [24, 25, 78]. In first, approach-autologous melanoma cell
lines were cultured with autologous peripheral blood to generate tumor-specific T cells
[152]. Adoptive transfers of T cells showed antitumor responses in melanoma patients.
Analysis of infused batches of T cells revealed the presence of polyclonal tumor-reactive
CD8 T and CD4 T cells [152]. Therefore, peripheral blood could be source material to
either expand neoantigen-specific T cells or generate novel clones that can effectively
induce tumor regression. In addition, technologies that would be able to purify
neoantigen-specific T cells would greatly aid ACTs with these cells [122, 153, 154].
Another approach could be to introduce TCR sequences of known specificities into
peripheral blood T cells. The feasibility of TCR gene engineering into patient’s
T cells have been demonstrated using TCRs directed against C/G antigens [25, 126,
155, 156]. Although cumbersome, ACTs with neoantigen-specific T cells have several
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benefits that are desirable to induce strong antitumor responses which cannot be currently envisioned with current generation cancer vaccines [25].
14. Concluding remarks
The aspirational goal of precision oncology is to find the right treatment for the
right patient. We have had significant success in discovering reliable response biomarkers
for many targeted therapies. For example, the presence of V600E mutation in the BRAF
gene is a reliable biomarker for prescribing BRAF inhibitors, such as vemurafenib and
dabrafenib, in melanoma patients. In comparison to precision-targeted therapy, precision
immunooncology is still in the developing phase. While there are numerous markers
shown to be enriched in tumors or peripheral blood of immunotherapy-responsive
patients, some unresponsive patients can also exhibit those markers. Furthermore, some
patients do not display these markers but, nonetheless, respond to immunotherapy. There
may be a benefit of an integrated biomarker approach where the likelihood of response is
gauged based on not just one marker, but rather a panel of immune parameters. Another
attractive approach to identify patients who are likely to benefit from immunotherapy is
to study early pharmacodynamic markers, such as an influx of T cells into the tumor
shortly after therapy administration. Lastly, highly personalized immunotherapeutic
approaches designed to target unique neoantigens of given tumors show promising early
results in patients, albeit high costs are limiting their widespread application. While personalized immune-oncology is still a work in progress, we look forward to the results of
many ongoing clinical studies testing a great number of promising biomarker candidates
that would enable tailoring immunotherapy to individual patient’s needs.
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